Device and method for intraocular drug delivery

ABSTRACT

Devices for delivering pharmaceutical formulations into the eye are described. The devices may be integrated to include features that allow safe and atraumatic manipulation of the devices with one hand. For example, accurate placement, including proper angulation, of the device on the eye and injection of a pharmaceutical formulation into the eye can be performed using one hand. The devices may also include improved safety features. For example, the devices may include an actuation mechanism that controls the rate and depth of injection into the eye. Some devices include a dynamic resistance component capable of adjusting the amount of pressure applied to the eye surface. Related methods and systems comprising the devices are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/341,582 filed on Mar. 31, 2010, U.S. Provisional Application Ser.No. 61/384,636 filed on Sep. 20, 2010, and U.S. Provisional ApplicationSer. No. 61/422,220 filed on Dec. 13, 2010, each of which is herebyincorporated by reference in its entirety.

FIELD

Described here are devices that are configured to safely and accuratelydeliver pharmaceutical formulations into the eye. Specifically, thedevices may integrate various features that allow easy manipulation ofthe devices, and which may be beneficial for positioning of the deviceson the ocular surface and for injecting pharmaceutical formulationsatraumatically within the eye. Systems and methods for intraocularlydelivering the pharmaceutical formulations using the devices are alsodescribed.

BACKGROUND

The eye is a complex organ comprised of many parts that enable theprocess of sight. Vision quality depends on the condition of eachindividual part and the ability of these parts to work together. Forexample, vision may be affected by conditions that affect the lens(e.g., cataracts), retina (e.g., CMV retinitis), or the macula (e.g.,macular degeneration). Topical and systemic drug formulations have beendeveloped to treat these and other ocular conditions, but each has itsdrawbacks. For example, topical therapies that are applied on thesurface of the eye typically possess short residence times due to tearflow that washes them out of the eye. Furthermore, delivery of drugsinto the eye is limited due to the natural barrier presented by thecornea and sclera, and additional structures if the intended targetresides within the posterior chamber. With respect to systemictreatments, high doses of drug are often required in order to obtaintherapeutic levels within the eye, which increases the risk of adverseside-effects.

Alternatively, intravitreal injections have been performed to locallydeliver pharmaceutical formulations into the eye. The use ofintravitreal injections has become more common due to the increasedavailability of anti-vascular endothelial growth factor agents for thetreatment of acute macular degeneration (AMD). Agents approved by theFDA for intravitreal injection to treat AMD include ranibizumab(Lucentis®: Genetech, South San Francisco, Calif.) and pegaptanib sodium(Macugen®: Eyetech Pharmaceuticals, New York, N.Y.). In addition,intravitreal bevacizumab (Avastin®: Genentech, South San Francisco,Calif.) has been widely used in an off-label application to treatchoroidal neovascularization. Increased interest in developing new drugsfor delivery directly into the vitreous for the treatment of macularedema, retinal vein occlusion, and vitreous hemorrhage also exists.

Currently, commercially available intravitreal injection devices lackmany features that are useful in exposing the site of injection,stabilizing the device against the sclera, and/or controlling the angleand depth of injection. Many of the devices described in the patentliterature, e.g., WO 2008/084064 and U.S. 2007/0005016, are also part ofmulti-component systems that are generally time consuming to set up anduse. The increased procedure time associated with these devices may inturn increase the risk of complications. Further, having to manipulatemany components by itself may increase the risk of complications due touser error. A serious complication of intraocular injection isintraocular infection, termed endophthalmitis that occurs due to theintroduction of pathogenic organisms such as bacteria from the ocularsurface into the intraocular environment, or trauma to the ocularsurface tissues such as corneal or conjunctival abrasion.

Accordingly, new devices for performing intravitreal injections would bedesirable. Ergonomic devices that simplify the injection procedure andreduce the risk of complications would be useful. Devices thataccurately and atraumatically inject drugs, e.g., liquid, semisolid, orsuspension-based drugs, into the eye would also be useful.

SUMMARY

Described here are devices, methods, and systems for deliveringpharmaceutical formulations into the eye. The devices may be integrated.By “integrated” it is meant that various features that may be beneficialin delivering the pharmaceutical formulations into the eye, e.g., in asafe, sterile, and accurate manner, are combined into a single device.For example, features that may aid appropriate placement on the desiredeye surface site, help position the device so that the intraocular spaceis accessed at the proper angle, help to keep the device tip stablewithout moving or sliding on the ocular surface once it has beenpositioned during the entire drug injection, adjust or controlintraocular pressure, and/or help to minimize trauma, e.g., from theforce of drug injection or contact or penetration of the eye wallitself, may be integrated into a single device. More specifically, theintegrated devices may be used in minimizing trauma due to directcontact with the target tissue or indirectly through force transmissionthrough another tissue or tissues such as the eye wall or vitreous gel,as well as minimizing trauma to the cornea, conjunctiva, episclera,sclera, and intraocular structures including, but not limited to, theretina, the choroid, the ciliary body, and the lens, as well as theblood vessels and nerves associated with these structures. Features thatmay be beneficial in reducing the risk of intraocular infectiousinflammation such as endophthalmitis and those that may reduce pain mayalso be included. It should be understood that the pharmaceuticalformulations may be delivered to any suitable target location within theeye, e.g., the anterior chamber or posterior chamber. Furthermore, thepharmaceutical formulations may include any suitable active agent andmay take any suitable form. For example, the pharmaceutical formulationsmay be a solid, semi-solid, liquid, etc. The pharmaceutical formulationsmay also be adapted for any suitable type of release. For example, theymay be adapted to release an active agent in an immediate release,controlled release, delayed release, sustained release, or bolus releasefashion.

In general, the devices described here include a housing sized andshaped for manipulation with one hand. The housing typically has aproximal end and a distal end, and an ocular contact surface at thehousing distal end. A conduit in its pre-deployed state will usuallyreside within the housing. The conduit will be at least partially withinthe housing in its deployed state. In some instances, the conduit isslidably attached to the housing. The conduit will generally have aproximal end, a distal end, and a lumen extending therethrough. Anactuation mechanism may be contained within the housing that is operablyconnected to the conduit and a reservoir for holding an active agent. Atrigger may also be coupled to the housing and configured to activatethe actuation mechanism. In one variation, a trigger is located on theside of the device housing in proximity to the device tip at the ocularcontact surface (the distance between the trigger and device tip rangingbetween 5 mm to 50 mm, between 10 mm to 25 mm, or between 15 mm to 20mm), so that the trigger can be easily activated by a fingertip whilethe device is positioned over the desired ocular surface site with thefingers of the same hand. In another variation, a trigger is located onthe side of the device housing at 90 degrees to a measuring component,so that when the device tip is placed on the eye surface perpendicularto the limbus, the trigger can be activated with the tip of the secondor third finger of the same hand that positions the device on the ocularsurface. In one variation, a measuring component is attached to theocular contact surface. In some variations, a drug loading mechanism isalso included.

The actuation mechanism may be manual, automated, or partiallyautomated. In one variation, the actuation mechanism is a spring-loadedactuation mechanism. Here the mechanism may include either a singlespring or two springs. In another variation, the actuation mechanism isa pneumatic actuation mechanism.

The application of pressure to the surface of the eye may beaccomplished and further refined by including a dynamic resistancecomponent to the injection device. The dynamic resistance component mayinclude a slidable element coupled to the housing. In some variations,the slidable element comprises a dynamic sleeve configured to adjust theamount of pressure applied to the eye surface. In other variations, thedynamic resistance component is configured as an ocular wall tensioncontrol mechanism.

In use, the devices deliver drug into the intraocular space bypositioning an ocular contact surface of the integrated device on thesurface of an eye, where the device further comprises a reservoir forholding an active agent and an actuation mechanism, and applyingpressure against the surface of the eye at a target injection site usingthe ocular contact surface, and then delivering an active agent from thereservoir into the eye by activating the actuation mechanism. The stepsof positioning, applying, and delivering are completed with one hand. Insome instances, a topical anesthetic is applied to the surface of theeye before placement of the device on the eye. An antiseptic may also beapplied to the surface of the eye before placement of the device on theeye.

The application of pressure against the surface of the eye using theocular contact surface may also generate an intraocular pressure rangingbetween 15 mm Hg to 120 mm Hg, between 20 mm Hg to 90 mm Hg, or between25 mm Hg to 60 mm Hg. As further described below, the generation ofintraocular pressure before deployment of the dispensing member(conduit) may reduce scleral pliability, which in turn may facilitatethe penetration of the conduit through the sclera, decrease unpleasantsensation associated with the conduit penetration through the eye wallduring an injection procedure and/or prevent backlash of the device.

The drug delivery devices, components thereof, and/or various activeagents may be provided in systems or kits as separately packagedcomponents. The systems or kits may include one or more devices as wellas one or more active agents. The devices may be preloaded or configuredfor manual drug loading. When a plurality of active agents is included,the same or different active agents may be used. The same or differentdoses of the active agent may be used as well. The systems or kits willgenerally include instructions for use. They may also include anestheticagents and/or antiseptic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B depict front views of exemplary ocular contact surfaces.

FIGS. 2A-2C show side views of additional exemplary ocular contactsurfaces that include measuring components.

FIGS. 3A1-3A3 and FIGS. 3B1-3B3 show side views of other exemplaryocular contact surfaces.

FIG. 4A and FIGS. 4B1-4B2 depict perspective and front views of anexemplary flanged ocular contact surface.

FIGS. 5A1-5A2 and FIGS. 5B1-5B2 depict side and perspective views ofexemplary flat and convex ocular contact surfaces.

FIGS. 6A1-6A2 and FIGS. 6B1-6B2 show side and front views of exemplarysoft or semi-solid ocular contact surfaces.

FIGS. 7A1-7A2, FIGS. 7B1-7B2, FIGS. 7C1-7C2, and FIGS. 7D-7E showadditional exemplary ocular contact surfaces, including ocular contactsurfaces having a high-traction interface.

FIG. 8 illustrates how an exemplary measuring component works to retractthe eyelid and measure a certain distance from the limbus.

FIGS. 9A-9C show exemplary arrangements of measuring components aroundan ocular contact surface.

FIGS. 10A-10C depict other exemplary measuring components and how theywork to measure a certain distance from the limbus.

FIGS. 11A-11D show further exemplary measuring components.

FIG. 12 shows an exemplary device that includes a marking tip member.

FIG. 13 illustrates how marks made on the surface of the eye by anexemplary marking tip member can be used to position the device at atarget injection site.

FIGS. 14A-14C show perspective views of exemplary sharp conduits.

FIGS. 15A1-15A2 show side views of exemplary bevel angles.

FIGS. 16A-16D depict cross-sectional views of exemplary conduitgeometries.

FIG. 17 depicts a cross-sectional view of additional exemplary conduitgeometries.

FIGS. 18A-18C show side and cross-sectional views (taken along line A-A)of an exemplary flattened conduit.

FIG. 19 shows an exemplary mechanism for controlling exposure of theconduit.

FIG. 20 provides another exemplary conduit exposure control mechanism.

FIG. 21 shows an exemplary device having a front cover and back cover.

FIG. 22 illustrates how the device may be filled with a pharmaceuticalformulation using an exemplary drug loading member.

FIGS. 23A-23C depict other examples of drug loading members.

FIGS. 24A-24D show an exemplary fenestrated drug loading member.

FIGS. 25A-25B show an exemplary fenestrated drug loading memberinterfaced with a drug source.

FIGS. 26A-26C depicts a side, cross-sectional view of an exemplarytwo-spring actuation mechanism.

FIG. 27 is a side, cross-sectional view of another exemplary two-springactuation mechanism.

FIG. 28 depicts a perspective view of a device including a furtherexample of a two-spring actuation mechanism in its pre-activated state.

FIG. 29 is a cross-sectional view of the device and two-spring actuationmechanism shown in FIG. 28.

FIG. 30 is a cross-sectional view of the device shown in FIG. 28 afterthe two-spring actuation mechanism has been activated.

FIGS. 31A-31C illustrate how the trigger in FIG. 28 actuates the firstspring of the two-spring actuation mechanism to deploy the conduit.

FIGS. 32A-32C are expanded views that illustrate how release of thelocking pins in FIG. 28 work to activate the second spring of thetwo-spring actuation mechanism.

FIGS. 33A-33B depict the device of FIG. 28 with an exemplary loadingport.

FIG. 34 is a perspective view of an exemplary device with a pneumaticactuation mechanism.

FIGS. 35A-35B provide cross-sectional views of the device shown in FIG.34. FIG. 35A show the pneumatic actuation mechanism in a pre-activatedstate. FIG. 35B shows the pneumatic actuation mechanism after deploymentof the conduit.

FIG. 36 is a cross-sectional view of an exemplary device including asingle spring actuation mechanism.

FIG. 37 is a cross-sectional view of the device shown in FIG. 36 thatshowing the single spring actuation mechanism after deployment of theconduit.

FIG. 38 is a side, cross-sectional view of an exemplary drug-loadingpiston.

FIGS. 39A-39I depict various views of exemplary device tips.

FIG. 40 shows an exemplary device with a sliding cap.

FIGS. 41A-41B provide cross-sectional views of another exemplary devicehaving a two-spring actuation mechanism.

FIG. 42 depicts an enlarged sectional view an exemplary dynamic sleeve.

FIGS. 43A-43D illustrate an exemplary method of advancement of adispensing member and drug injection.

FIGS. 44A-44D depict exemplary positional indicator components.

FIGS. 45A-45J show various aspects of exemplary fine sleeve mobilitycontrol components.

FIG. 46 is a graphic depiction of the amount of resistance forcegenerated by a dynamic sleeve according to one variation.

DETAILED DESCRIPTION

Described here are hand-held devices, methods, and systems fordelivering, e.g., by injection, pharmaceutical formulations into theeye. The devices may integrate (combine) various features that may bebeneficial in delivering the pharmaceutical formulations into the eye,e.g., in a safe, sterile, and accurate manner, into a single device.Thus, features that may aid appropriate placement on the eye, helppositioning so that the intraocular space is accessed at the properangle, adjust or control intraocular pressure, and/or help to minimizetrauma to the sclera and intraocular structures, e.g., from the force ofinjection or penetration of the sclera itself, may be integrated into asingle device. The devices, in whole or in part, may be configured to bedisposable.

I. DEVICES

In general, the integrated devices described here include a housingsized and shaped for manipulation with one hand. The housing typicallyhas a proximal end and a distal end, and an ocular contact surface atthe housing distal end. A conduit tin its pre-deployed state may residewithin the housing. The conduit will be at least partially within thehousing in its deployed state. In some variations, the conduit isslidably attached to the housing. Additionally, the conduit willgenerally have a proximal end, a distal end, and a lumen extendingtherethrough. An actuation mechanism may be contained within the housingthat is operably connected to the conduit and a reservoir for holding anactive agent.

The devices or portions thereof may be formed from any suitablebiocompatible material or combination of biocompatible materials. Forexample, one or more biocompatible polymers may be used to make, e.g.,the device housing, ocular contact surface, measuring component, etc.Exemplary biocompatible and non-biodegradable materials include withoutlimitation, methylmethacrylate (MMA), polymethylmethacrylate (PMMA),polyethylmethacrylate (PEM), and other acrylic-based polymers;polyolefins such as polypropylene and polyethylene; vinyl acetates;polyvinylchlorides; polyurethanes; polyvinylpyrollidones;2-pyrrolidones; polyacrylonitrile butadiene; polycarbonates; polyamides;fluoropolymers such as polytetrafluoroethylene (e.g., TEFLON™ polymer);polystyrenes; styrene acrylonitriles; cellulose acetate; acrylonitrilebutadiene styrene; polymethylpentene; polysulfones; polyesters;polyimides; natural rubber; polyisobutylene rubber; polymethylstyrene;silicone; and copolymers and blends thereof.

In some variations, the device or a portion of the device such as thedrug reservoir, plunger, housing, ocular contact surface, or measuringcomponent, is made of a material that includes a cyclic olefin seriesresin. Exemplary cyclic olefin resins include without limitation,commercially available products such as Zeonex® cyclo olefin polymer(ZEON Corporation, Tokyo, Japan) or Crystal Zenith® olefinic polymer(Dalkyo Seiko, Ltd., Tokyo, Japan) and APEL™ cyclo olefin copolymer(COC) (Mitsui Chemicals, Inc., Tokyo, Japan), a cyclic olefin ethylenecopolymer, a polyethylene terephthalate series resin, a polystyreneresin, a polybutylene terephthalate resin, and combinations thereof. Inone variation, it may be beneficial to use a cyclic olefin series resinand a cyclic olefin ethylene copolymer that have high transparency, highheat resistance, and minimal to no chemical interaction with apharmacological product such as a protein, a protein fragment, apolypeptide, or a chimeric molecule including an antibody, a receptor ora binding protein.

The cyclic olefin polymers or the hydrogenation products thereof can bering-opened homopolymers of cyclic olefin monomers, ring-openedcopolymers of cyclic olefin monomers and other monomers, additionhomopolymers of cyclic olefin monomers, addition copolymers of cyclicolefin monomers and other monomers, and hydrogenation products of suchhomopolymers or copolymers. The above cyclic olefin monomers may includemonocyclic olefin monomers, and polycyclic olefin monomers includingbicyclic and higher cyclic compounds. Examples of the monocyclic olefinmonomers suitable for the production of the homopolymers or copolymersof the cyclic olefin monomers are monocyclic olefin monomers such ascyclopentene, cyclopentadiene, cyclohexene, methylcyclohexene andcyclooctene; lower-alkyl derivatives thereof containing, as substituentgroups, 1 to 3 lower alkyl groups such as methyl and/or ethyl groups;and acrylate derivatives thereof.

Examples of the polycyclic olefin monomers are dicyclopentadiene,2,3-dihydrocyclopentadiene, bicyclo[2,2,1]-hepto-2-ene and derivativesthereof, tricyclo[4,3,0,1^(2,5)]-3-decene and derivatives thereof,tricyclo[4,4,0,1^(2,5)]-3-undecene and derivatives thereof,tetracyclo[4,4,0,1^(2,5),0^(7,10)]-3-dodecene and derivatives thereof,pentacyclo[6,5,1,1^(3,6),0^(2,7),0^(9,13) 4-pentadecene and derivativesthereof, pentacyclo[7,4,0,1^(2,5,0),0^(8,13),1^(9,12)]-3-pentadecene andderivatives thereof, andhexacyclo[6,6,1,1^(3,6),1^(10,13),0^(2,7),0^(9,14)]-4-heptadecene andderivatives thereof. Examples of bicyclo[2,2,1]-hepto-2-ene derivativesinclude 5-methyl-bicyclo[2,2,1]-hepto-2-ene,5-methoxy-bicyclo[2,2,1]-hepto-2-ene,5-ethylidene-bicyclo[2,2,1]-hepto-2-ene,5-phenyl-bicyclo[2,2,1]-hepto-2-ene, and6-methoxycarbonyl-bicyclo[2,2,1-]-hepto-2-ene. Examples oftricyclo[4,3,0,1^(2,5)]-3-decene derivatives include2-methyl-tricyclo[4,3,0,1^(2,5)]-3-decene and5-methyl-tricyclo[4,3,0,1^(2,5)]-3-decene. Examples oftetracyclo[4,4,0,1^(2,5)]-3-undecene derivatives include10-methyl-tetracyclo[4,4,0,1^(2,5)]-3-undecene, and examples oftricyclo[4,3,0,1^(2,5)]-3-decene derivatives include5-methyl-tricyclo[4,3,0,1^(2,5)]-3-decene.

Examples of tetracyclo[4,4,0,1^(2,5),0^(7,10)]-3-dodecene derivativesinclude 8-ethylidene-tetracyclo-[4,4,0,1^(2,5),0^(7,10)]-3-dodecene,8-methyl-tetracyclo-[4,4,0,1^(2,5),0^(7,10)]-3-dodecene,9-methyl-8-methoxy-carbonyl-tetracyclo[4,4,0,1^(2,5),0^(7,10)]-3-dodecene,5,10-dimethyl-tetracyclo[4,4,0,1^(2,5),0^(7,10)]-3-dodecene. Examples ofhexacyclo[6,6,1,1^(3,6),1^(10,13),0^(2,7),0^(9,14)]-4-heptadecenederivatives include12-methyl-hexacyclo[6,6,1,1^(3,6),1^(10,13),0^(2,7),0^(9,14)]-4-heptadeceneand 1,6-dimethyl-hexacyclo[6,6,1,1^(3,6),1^(10,13),0^(2,7),0^(9,14)]-4-heptadecene. One example of the cyclic olefin polymer is anaddition homopolymer of at least one cyclic olefin monomer or anaddition copolymer of at least one cyclic olefin monomer and at leastone other olefin monomer (for example, ethylene, propylene,4-methylpentene-1, cyclopentene, cyclooctene, butadiene, isoprene,styrene, or the like). This homopolymer or copolymer can be obtained bypolymerizing the above monomer or monomers, for example, while using asa catalyst a known catalyst which is soluble in a hydrocarbon solventand is composed of a vanadium compound or the like and an organoaluminumcompound or the like (Japanese Patent Application Laid-Open (Kokai) No.HEI 6-157672, Japanese Patent Application Laid-Open (Kokai) No. HEI5-43663).

Another example of the cyclic olefin polymer is a ring-openedhomopolymer of the above monomer or a ring-opened copolymer of the abovemonomers. It can be obtained by homopolymerizing the above monomer orcopolymerizing the above monomers, for example, while using as acatalyst a known catalyst such as (1) a catalyst composed of a halide orthe nitrate of a platinum group metal such as ruthenium, rhodium,palladium, osmium or platinum and a reducing agent or (2) a catalystcomposed of a compound of a transition metal such as titanium,molybdenum or tungsten and an organometal compound of a metal in one ofGroups I to IV of the periodic table such as an organoaluminum compoundor organotin compound (Japanese Patent Application Laid-Open (Kokai) No.HEI 6-157672, Japanese Patent Application Laid-Open (Kokai) No. HEI5-43663).

The homopolymer or copolymer may contain unsaturated bonds. Thehomopolymer or copolymer may be hydrogenated using a known hydrogenationcatalyst. Examples of the hydrogenation catalyst include (1)Ziegler-type homogeneous catalysts which are each composed of an organicacid salt of titanium, cobalt, nickel or the like and an organometalcompound of lithium, aluminum or the like, (2) supported catalysts whichare each composed of a carrier such as carbon or alumina and a platinummetal such as palladium or ruthenium supported on the carrier, and (3)catalysts which are each composed of a complex of one of theabove-described platinum group metal (Japanese Patent ApplicationLaid-Open (Kokai) No. HEI 6-157672).

In some variations, the device or a portion of the device such as thedrug reservoir is made of a material that comprises a rubber. Examplesof suitable rubber materials include butyl rubbers such as butyl rubber,chlorinated butyl rubber, brominated butyl rubber, anddivinylbenzene-copolymerized butyl rubber; conjugated diene rubbers suchas polyisoprene rubber (high to low cis-1,4 bond), polybutadiene rubber(high to low cis-1,4 bond), and styrene-butadiene copolymer rubber; andethylene-propylene-diene terpolymer rubber (EPDM). Crosslinkable rubbermaterials may also be used, and may be made by kneading theabove-described rubber materials together with additives such as acrosslinking agent, a filler and/or reinforcement, a colorant, or an ageresister.

In some variations, the biocompatible material is a biodegradablepolymer. Non-limiting examples of suitable biodegradable polymersinclude cellulose and ester, polyacrylates (L-tyrosine-derived or freeacid), poly(β-hydroxyesters), polyamides, poly(amino acid),polyalkanotes, polyalkylene alkylates, polyalkylene oxylates,polyalkylene succinates, polyanhydrides, polyanhydride esters,polyaspartimic acid, polylactic acid, polybutylene digloclate,poly(caprolactone), poly(caprolactone)/poly(ethylene glycol) copolymers,polycarbone, L-tyrosin-derived polycarbonates, polycyanoacrylates,polydihydropyrans, poly(dioxanone), poly-p-dioxanone,poly(ε-caprolactone-dimethyltrimethylene carbonate), poly(esteramide),polyesters, aliphatic polyesters, poly(etherester), polyethyleneglycol/poly(orthoester) copolymers, poly(glutarunic acid), poly(glycolicacid), poly(glycolide), poly(glycolide)/poly(ethylene glycol)copolymers, poly(lactide), poly(lactide-co-caprolactone),poly(DL-lactide-co-glycolide), poly(lactide-co-glycolide)/poly(ethyleneglycol) copolymers, poly(lactide)poly(ethylene glycol) copolymers,polyphosphazenes, polyphosphesters, polyphophoester urethanes,poly(propylene fumarate-co-ethylene glycol), poly(trimethylene carbone),polytyrosine carbonate, polyurethane, terpolymer (copolymers ofglycolide lactide or dimethyltrimethylene carbonate), and combinations,mixtures or copolymers thereof.

Additives may be added to polymers and polymer blends to adjust theirproperties as desired. For example, a biocompatible plasticizer may beadded to a polymer formulation used in at least a portion of a device toincrease its flexibility and/or mechanical strength, or to provide colorcontrast with respect to the surface of the eye. In other instances, abiocompatible filler such as a particulate filler, fiber and/or mesh maybe added to impart mechanical strength and or rigidity to a portion of adevice.

The devices described here can be manufactured, at least in part, byinjection or compression molding the above-described materials.

In some instances, it may be beneficial to include a removably attachedor integrated viewing and/or magnifying element on the device. Forexample, a magnifying glass and/or illumination source such as a LEDlight may be removably attached to the device to facilitate thevisualization of the tip of the device and the injection site. Theimproved visualization may help to more precisely and safely positionthe device at a target location, e.g., about 3.5 mm to 4 mm posterior tothe corneo-scleral limbus, so that complications of intraocularinjection such as retinal detachment, ciliary body bleeding, or traumato the intraocular lens can be potentially avoided. The magnifying glassmay be made from any suitable material, e.g., it may be made from anysuitable non-resorbable (biodegradable) material previously described,but will typically be light-weight so that it does not affect thebalance of the injection device. The magnifying glass and/orillumination source, e.g., the LED, may be disposable.

Housing

The housing of the device generally contains the drug reservoir andactuation mechanism. In its first, non-deployed state (pre-deployedstate), the conduit may reside within the housing. The housing may be ofany suitable shape, so long as it allows grasping and manipulation ofthe housing with one hand. For example, the housing may be tubular orcylindrical, rectangular, square, circular, or ovoid in shape. In somevariations, the housing is tubular or cylindrical, similar to the barrelof a syringe. In this instance, the housing has a length between about 1cm and about 15 cm, between about 2.5 cm and about 10 cm, or about 4 cmand about 7.5 cm. For example, the housing may have a length of about 1cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about13 cm, about 14 cm, or about 15 cm. The surface of the housing may alsobe texturized, roughened, or otherwise modified in certain areas, e.g.,with protrusions, ridges, etc., to aid the grip and or manipulation ofthe housing by the user.

The housing may be made from any suitable material. For example, and aspreviously stated, the components of the device may be made from anysuitable biocompatible material or combination of biocompatiblematerials. Materials that may be beneficial in making the housinginclude, without limitation, a cyclic olefin series resin, a cyclicolefin ethylene copolymer, a polyethylene terephthalate series resin, apolystyrene resin, and a polyethylene terephthalate resin. In onevariation, it may be beneficial to use a cyclic olefin series resin anda cyclic olefin ethylene copolymer that have a high transparency, a highheat resistance, and minimal to no chemical interaction with apharmacological product such as a protein, a protein fragment, apolypeptide, or a chimeric molecule including an antibody, a receptor ora binding protein. Additional materials that may be beneficial in makingthe housing include, without limitation, fluoropolymers; thermoplasticssuch as polyetheretherketone, polyethylene, polyethylene terephthalate,polyurethane, nylon, and the like; and silicone. In some variations, thehousing may be made from a transparent material to aid confirmation ofconduit deployment and/or drug delivery. Materials with suitabletransparency are typically polymers such as acrylic copolymers,acrylonitrile butadiene styrene (ABS), polycarbonate, polystyrene,polyvinyl chloride (PVC), polyethylene terephthalate glycol (PETG), andstyrene acrylonitrile (SAN). Acrylic copolymers that may be usefulinclude, but are not limited to, polymethyl methacrylate (PMMA)copolymer and styrene methyl methacrylate (SMMA) copolymer (e.g., Zylar631® acrylic copolymer).

Ocular Contact Surfaces

The devices described herein generally include an atraumatic ocularcontact surface at the distal end of the housing. In some variations,the ocular contact surface is fixedly attached to the housing proximalend. In other variations, the ocular contact surface is removablyattached to the housing proximal end. The ocular contact surface willtypically be sterile. In some instances, the ocular contact surface isdisposable. In use, the ocular contact surface of the device is placedon the surface of the eye.

The ocular contact surface may be of any suitable configuration, e.g.,size, shape, geometry, etc., as long as it allows atraumatic placementof the device on the ocular surface. In some variations, the ocularcontact surface is ring-shaped (e.g., FIGS. 1A-1B). When the ocularcontact surface takes the shape of a ring, it may have a diameter ofabout 0.3 mm to about 8 mm, about 1 mm to about 6 mm, or about 2 mm toabout 4 mm. In other variations, the ocular contact surface is oval orcircular in shape.

More specifically, as shown in the front views of FIGS. 1A-1B, thedevice tip comprises a ring-shaped ocular contact surface where thedistance between the inner diameter and outer diameter of the ring formsa rim. In this instance, the ring-shaped ocular contact surface may beconfigured as having a wider ocular contact surface (10) (rim) andsmaller internal opening (12) (FIG. 1A), or narrower ocular contactsurface (14) (rim) with larger internal opening (16) (FIG. 1B). Thedispensing member (conduit) may be an injection needle that is hiddeninside and protected by the device tip. A membrane may also be providedthat extends across the internal opening, and which may be flush withthe ocular contact surface or recessed within the lumen of the devicetip where the injection needle resides.

As shown in FIGS. 39A-39B, the tip of the dispensing member may berecessed relative to end of the device housing tip comprising the ocularcontact surface in the resting state, so that when the device tip isplaced in contact with any surface such as the skin or the eye wall, thetip of the dispensing member is separated from the surface by a distancemarked with arrows in FIG. 39B. This distance may ensure that thedispensing member tip does not come in direct contact with any surfaceprior to the injection procedure, which prevents accidental bacterialcontamination of the dispensing member from sources such as skinsecretions, ocular secretions or tears, and minimizes the risk ofintroducing intraocular infectious agents during the intraocularinjection procedure that may cause endophthalmitis.

In some variations, the tip of the dispensing member is recessedrelative to, and is separated from the closest end of the device housingby a distance ranging from about 0.01 mm to about 10 mm, from about 0.1mm to about 5 mm, or from about 0.5 mm to about 2 mm.

In another variation, the ocular contact surface of the device tip thatcomes in direct contact with the eye surface is ring-shaped, where thereis a clearing between the internal wall of the device housing and thedispensing member of about 360 degrees, which is marked by arrows inFIG. 39C. Here, if the ring-shaped ocular interface surface becomescontaminated with an infectious agent and is placed onto the eyesurface, the dispensing member will come in contact and penetratethrough the eye surface that is separated from the contaminated devicetip by the area of clearing, which prevents accidental bacterialcontamination of the dispensing member and minimizes the risk ofintroducing intraocular infection that may cause endophthalmitis. Incontrast, the lack of such clearing around the dispensing member, asshown in FIG. 39D, may allow accidental infectious contamination of thedevice tip at the site of injection.

In some variations, there is a clearing between the internal wall of thedevice housing and the dispensing member ranging from about 0.1 mm toabout 5 mm, from about 0.3 mm to 3 mm, or from about 0.5 mm to about 2mm.

In other variations, there is a solid membrane or partition (105) thatseparates the tip of the dispensing member (107) from the externalenvironment, as shown in FIG. 39E, where the membrane or partition maybe water-impermeable and/or be air-impermeable. The membrane orpartition may ensure that there is no air movement in or out of thedevice creating an air seal and maintaining a certain constant airpressure inside the device.

Furthermore, the membrane or partition may ensure that the dispensingmember tip does not come in contact with any source of accidentalbacterial contamination such as tears and ocular secretions prior to theinjection procedure, which prevents accidental bacterial contaminationof the dispensing member and minimizes the risk of introducingintraocular infection during the intraocular injection procedure thatmay cause endophthalmitis.

The membrane or partition that separates the tip of the dispensingmember from the end of the device housing may comprise a materialselected from the group consisting of biocompatible andnon-biodegradable materials including without limitation,methylmethacrylate (MMA), polymethylmethacrylate (PMMA),polyethylmethacrylate (PEM), and other acrylic-based polymers;polyolefins such as polypropylene and polyethylene; vinyl acetates;polyvinylchlorides; polyurethanes; polyvinylpyrollidones;2-pyrrolidones; polyacrylonitrile butadiene; polycarbonates; polyamides;fluoropolymers such as polytetrafluoroethylene (e.g., TEFLON™ polymer);or fluorinated ethylene propylene (FEP); polystyrenes; styreneacrylonitriles; cellulose acetate; acrylonitrile butadiene styrene;polymethylpentene; polysulfones; polyesters; polyimides; natural rubber;polyisobutylene rubber; polymethylstyrene; silicone; derivatives andcopolymers and blends thereof.

In some variations, the membrane or partition (30) may be recessedinside the device tip so that when the device tip is placed in contactwith any surface such as the skin or the eye surface, the said membraneor partition is separated from the said surface by a distance markedwith arrows, as depicted in FIG. 39E. The distance may ensure that thedispensing member tip (31) does not come in direct contact with anysurface prior to the injection procedure, which prevents accidentalbacterial contamination of the dispensing member from sources such asskin secretions, ocular secretions or tears, and minimizes the risk ofintroducing intraocular infection during the intraocular injectionprocedure that may cause endophthalmitis.

The membrane or partition may be recessed relative to and separated fromthe end of the device housing at the ocular interface by a distanceranging from about 0.01 mm to about 10 mm, from about 0.1 mm to about 5mm, or from about 0.5 mm to about 2 mm.

In further variations, a measuring component (32) (further describedbelow) may be recessed relative to the end of the device housing (33) atthe ocular contact surface (FIGS. 39F-39H), so that when the device tip(34) comes in contact with the eye surface (35) (FIG. 39I), themeasuring component (32) does not come in contact with the eye surface(35). This configuration may minimize the risk of trauma to the delicatetissue covering the eye surface such as the non-keratinizing epitheliaof the cornea and conjunctiva. Avoiding direct contact between themeasuring member and the ocular surface may be beneficial in minimizingthe risk of ocular surface trauma such as corneal or conjunctivalabrasion, which prevents further serious complications such as bacterialinjection including corneal ulcer. In alternative variations, the tip ofthe measuring member (32) may be angled away or towards the eye (FIGS.39G and 39H, respectively). The measuring component may be recessedrelative to the end of the device housing by a distance ranging fromabout 0.01 mm to about 5 mm, from about 0.1 mm to about 3 mm, or fromabout 0.5 mm to about 2 mm.

In some variations, as shown in FIGS. 2A-2C, the device tip may alsocomprise a ring-shaped ocular contact surface and a measuring means thathelps to determine the proper location of the injection site at acertain distance relative to and perpendicular to the corneo-sclerallimbus. In one variation, the measuring component (20) is located on oneside of the device tip (22). In another variation, more than onemeasuring component is located on more than one side of the device tip.Here the tip of the measuring component is flat (FIG. 2C) and does notsubstantially protrude above the ocular contact surface. In othervariations, the tip of the measuring component is raised (FIGS. 2A-2B)above the ocular contact surface, which enables it to prevent the eyelidfrom sliding over and on top of the measuring component, thus preventingthe eyelid from coming into contact with the sterile ocular contactsurface of the device tip or the dispensing member. This in turn mayreduce the risk of accidental contamination and intraocular infectionduring the injection procedure.

In other variations, the ocular contact surface comprises a flange(e.g., FIGS. 3A1-3A3, FIGS. 3B1-3B3, FIG. 4A, and FIGS. 4B1-4B2). Theflange may provide an expanded contact surface between the device tipand the eye surface, thus increasing the stability of the device when itis positioned on the ocular surface, and decreasing the pressure forceper unit area of the device-ocular interface. Reducing the pressureforce per unit area of the device-ocular interface in turn may reducethe potential for conjunctival damage by the device tip when it ispressed against the eye wall. Avoiding such conjunctival damage isdesirable because the conjunctiva is covered by delicatenon-keratinizing epithelium containing multiple sensory nerve endingsand pain receptors.

In some variations, the flange may have thin edges that come in contactwith the ocular surface, and which allows the eye lid to travel over andon top of the flange, but prevents the eye lid from coming in contactwith the sterile ocular contact surface of the device tip. The ocularcontact surface may also be a ring-shaped flange (e.g., FIGS. 4A and4B1-4B2). Such a ring-shaped flange may also prevent the eye lid fromcoming in contact with the sterile ocular contact surface of the devicetip.

More specifically, as shown in FIG. 3, the flange may have a thin edge(FIG. 3A1), which allows the eye lid to slide over the said flange andcome in contact with the shaft of the device tip. In an alternativevariation, the said flange may be thick (FIG. 3B1) in order to preventthe eye lid from sliding over it and keeping it from coming in contactwith the device shaft, thus preventing inadvertent contamination of theinjection site. When the flange at the ocular contact surface of thedevice tip is thick, its edges, such as those at its ocular surface maybe rounded in order to prevent accidental damage to the ocular surfacetissues such as the conjunctiva that is covered with delicatenon-keratinizing epithelium rich in nerve endings and pain receptors. Inalternative variations of the device tip, the ocular contact interfacemay be flat (FIGS. 3A1 and 3B1), convex (FIGS. 3A2 and 3B2), or concave(FIGS. 3A3 and 3B3) to reduce the chance of accidental damage to ocularsurface tissues such as the conjunctiva while providing a means ofapplying a force onto the eye wall and increasing intraocular pressurein order to facilitate the needle penetration through the eye wall, aswell as to partially immobilize the eye during the injection procedureby providing the traction interface of the ocular contact surface. FIGS.4A and 4B1-4B2 illustrate perspective and front views of a flangedocular contact surface.

In yet further variations, the ocular contact surface may be configuredto be flat, convex, concave, or slanted (e.g., FIGS. 5 and 7). In FIGS.5A1-5A2, the device tip has a flat ocular contact surface. In analternative variation, the device tip has a protruding or convex ocularcontact surface (FIGS. 5B1-5B2), which may improve contact between theinternal opening of the device tip and the ocular surface when thedevice tip is pressed against the eye wall resulting in eye wallindentation. In yet another variation, the ocular contact surface of thedevice tip is indented or concave, which reduces the risk of accidentaldamage to the ocular surface tissue such as the conjunctiva. Suchconfigurations of the ocular contact surface of the device tip mayreduce the chance of accidental damage to ocular surface tissues, suchas the conjunctiva, while providing a means of applying a pressure forceonto the eye wall and increasing the intraocular pressure in order tofacilitate the needle penetration through the eye wall, as well as topartially immobilize the eye during the injection procedure by providingthe device-ocular surface traction interface.

More specifically, as shown in FIG. 7, the ocular contact surface may beflat and perpendicular to the long axis of the said device (FIGS.7A1-7A2), or is flat and slanted relative to the long axis of the saiddevice (7B1-7B2) (e.g., oriented at an angle other than 90 degrees, suchas from about 45 degrees to about 89 degrees relative to the long axisof the device), or is convex and perpendicular to the long axis of thedevice (FIG. 7C1), or is convex and slanted relative to the long axis ofthe device (FIG. 7C2), or is rounded (FIG. 7D), or is oval (FIG. 7E). Inone variation, the ocular interface is rounded or oval (e.g., similar tothe tip of a Q-tip). The thickness of the ocular contact surface may befrom about 0.01 mm to about 10 mm, from about 0.05 mm to about 5 mm, orfrom about 0.1 mm to about 2 mm.

The ocular contact surface may include one or more features that help tostabilize it on the eye surface. For example, in one variation, theocular contact surface comprises a plurality of traction elements, e.g.,bumps, ridges, etc., that increase surface traction of the ocularcontact surface on the eye surface without being abrasive. Such anocular contact surface may provide a medium- or high-traction interfaceto stabilize the device on the surface of the eye and prevent it frommoving during intraocular drug delivery. In another variation, theocular contact surface includes an adherent interface such as a suctionmechanism. Varying the type of material used to make the ocular contactsurface may also help prevent its slippage on the ocular surface.

The materials used to make the ocular contact surface may also help toprevent abrasion, scratching, or irritation of the eye surface.Exemplary non-abrasive materials that may be employed include withoutlimitation, nylon fiber, cotton fiber, hydrogels, spongiform materials,styrofoam materials, other foam-like materials, silicone, plastics,PMMA, polypropylene, polyethylene, fluorinated ethylene propylene (FEP),and polytetrafluoroethylene (PTFE). These materials may be smooth-hard,semi-hard, or soft, and may be beneficial in preventing conjunctivalabrasion, subconjunctival hemorrhage during transcleral needledeployment, or other accidental trauma to the ocular surface tissues(FIG. 6). Materials typically used in contact lens manufacturing mayalso be employed.

In some variations, the edges of the ocular contact surface are alsorounded to prevent accidental damage to the ocular surface tissues suchas the conjunctiva that is covered with delicate non-keratinizingepithelium rich in nerve endings and pain receptors. In this instance,as shown in FIG. 6, the ocular contact surface may have a circumferencecorresponding to the circumference of the device tip (FIGS. 6A1-6A2). Inother variations, the circumference of the ocular contact surface mayprotrude beyond the circumference of the shaft of the device tip, thusforming a flange (FIGS. 6B1-6B2). The flange may increase the ocularcontact surface of the device tip while maintaining the slim profile ofthe shaft of the tip, enabling its easy insertion into theinterpalprebral fissure of the eye.

The ocular contact surface may also provide an interface surface that ispliable or deformable, and which conforms to the surface of the eye whenplaced against the said eye surface during the intraocular drug deliveryprocedure. The surface of the eye that comes in direct contact with thesaid interface surface of the disclosed device includes, but is notlimited to, the surface of the eye over the pars plana region defined asthe circumferential area between about 2 mm and 7 mm posterior to andsurrounding the limbus, or the corneo-scleral limbal area between about2 mm anterior and about 2 mm poster to and circumferential to thelimbus. The interface surface that conforms to the curvature of thesurface of the eye may enable the formation of an optimal contactinterface between the device and the eye, and may ensure sterility ofthe intraocular drug delivery process and immobilization of the eye,which in turn may enhance the safety of the injection procedure.Examples of ocular interface materials for the device are those that aregenerally able to conform to the surface of the eye (that is deformableor pliable) particularly to the curvature of the external surface of theeye in the area of pars plana about 2-5 mm posterior to thecorneo-scleral limbus for intravitreal drug application, as well as tothe area of the corneo-scleral limbus for anterior chamber drugapplications. As previously stated, materials that are non-abrasive tothe non-keratinizing conjunctival and corneal epithelium of the ocularsurface may be used. Specifically, the materials and theirconfigurations (e.g., foam, braid, knit, weave, fiber bundle, etc.), mayinclude those capable of forming medium- or high-traction surfaces(e.g., hydrogels or cotton) that enable immobilization of the eye globeduring the injection procedure.

In some variations, the material of the ocular contact surface changesits properties upon contact with fluid, e.g., by reducing its tractioncoefficient such as in cotton fiber, which may reduce the risk ofconjunctival abrasion upon contact of the ocular contact surface withthe eye surface. In other variations, the material comprising ocularcontact surface does not change its physical and chemical propertieswhen exposed to fluid that covers the surface of the eye such as tears.

The ocular contact surfaces described here may be beneficial inpreventing conjunctival and/or episcleral bleeding during intraocularneedle injection. For example, a device comprising a ring-shaped ocularinterface may be pressed against the eye wall, which in turn appliespressure to the conjunctival and episcleral vessels, thereby reducingblood flow therethrough. Given the reduced blood flow through thesevessels, the risk of subconjunctival bleeding during intraocularinjection procedure may be reduced. Following the completion ofintraocular drug application, the needle is withdrawn, but thering-shaped tip may remain pressed against the eye wall, thus applyingcontinuous pressure onto the conjunctival and episcleral vessels andfurther reducing the risk of bleeding and/or minimizing the extent ofbleeding.

In some variations, the device comprises an ocular contact surface thatfunctions as a drug reservoir. Here a drug may be incorporated into, orcoated on, the material of the ocular contact surface. The drug may thendiffuse, leech, etc., from the ocular contact surface onto the surfaceof the eye. Exemplary materials for inclusion of drugs are hydrogels andtheir derivatives.

The ocular contact surface may also cover the dispensing member(conduit) such as an injection needle (e.g., it may be a cap thatentirely covers the needle), which may enable the injector to applypressure onto the eye by pressing the tip (e.g., the distal end of thecap) against the eye wall. This in turn may increase the intraocularpressure before the needle comes in contact with the eye wall and, thus,may facilitate needle penetration because the eye wall is more taut incomparison to an eye wall being penetrated by a needle on a conventionalsyringe. Needle penetration is typically more difficult with aconventional syringe because the lower intraocular pressure that isgenerated makes the eye wall more deformable and mobile. In addition,the device tip that covers the dispensing member (conduit), such as aninjection needle, may also protect the said dispensing member from beingcontaminated by its accidental contact with eye lids.

Intraocular Pressure Control Mechanisms (Ocular Wall Tension ControlMechanisms)

The control of intraocular pressure (IOP) during the drug deliveryprocedure, e.g., intraocular injection or intravitreal injection, may bebeneficial. The application of limited intraocular pressure beforedeployment of the dispensing member (conduit) may reduce scleralpliability, which in turn may decrease any unpleasant sensation on theeye surface during an injection procedure and/or prevent backlash of thedevice. The term “backlash” typically refers to the inability of theconduit to smoothly penetrate the eye wall due to scleral pliability andelasticity, which makes the sclera indent to a certain point and pushthe conduit and device backwards before the conduit penetrates into andthrough the sclera. Accordingly, the devices described here may includeone or more IOP control mechanisms, also referred to herein as ocularwall tension control mechanisms. This is because ocular wall tension isproportionally related to, and determined in part, by intraocularpressure. Other factors that may effect wall tension are scleralthickness and rigidity, which can be variable due to patient age,gender, and individual variations.

The IOP mechanisms may control IOP during the placement and positioningof the device tip at the target location on the ocular surface, and/orintraocular or intravitreal positioning of the dispensing member(conduit) during intraocular or intravitreal injection of a drug. Forexample, the IOP mechanisms may control IOP prior to and during theintraocular or intravitreal positioning of a dispensing member beingused for trans-scleral or trans-corneal penetration. Once penetration ofthe ocular surface by the dispensing member occurs, IOP will typicallydecrease. This decrease in IOP may occur immediately after penetrationof the ocular surface by the dispensing member.

In some variations, the IOP control mechanisms allow (enable) thedevices to generate an IOP between 15 and 120 mm Hg during the placementand positioning of the device tip at a target location on the ocularsurface, and/or intraocular positioning of the dispensing member. Inother variations, the IOP control mechanisms allow (enable) the devicesto generate an IOP between 20 and 90 mm Hg during the placement andpositioning of the device tip at a target location on the ocularsurface, and/or intraocular positioning of the dispensing member. In yetfurther variations, the IOP control mechanisms allow (enable) thedevices to generate an IOP between 25 and 60 mm Hg during the placementand positioning of the device tip at a target location on the ocularsurface, and/or intraocular positioning of the dispensing member.

The IOP control mechanisms may also allow (enable) the devices tomaintain the IOP between 10 and 120 mm Hg, or between 15 and 90 mm Hg,or between 20 and 60 mmHg during any duration of time of the intraocularinjection procedure. In some variations, the drug injection rate isslowed or completely aborted by the device if the intraocular pressureexceeds a certain predetermined value, for example 120 mm Hg, or 60 mmHg, or 40 mm Hg. Here the IOP control mechanism may be configured todetect a IOP level during the intraocular drug injection of, e.g., 90mmHg, or 60 mm Hg, or 40 mm Hg.

The IOP control mechanism may include a spring, or it may comprise amechanical or an electrical control mechanism. In general, the IOPcontrol mechanism will be configured to balance the frictional forces ofthe injection plunger and fluid injection resistance pressure (forcerequired to push fluid through the needle into the pressurized eyefluids). The IOP control mechanisms may be coupled to the device housingand actuation mechanism in a manner that allows automatic adjustment ofthe force of dispensing member deployment and plunger advancement. Thatis, the IOP control mechanism may be configured to effect apredetermined level of force of the dispensing member and apredetermined intraocular pressure level. Again, use of the IOP controlmechanisms may generate higher than the resting IOP prior to dispensingmember deployment so that scleral elasticity and the potential fordevice backlash is decreased, and to facilitate scleral penetration bythe dispensing member.

In one variation, the IOP control mechanism is a pressure relief valvethat bypasses the injection stream once a maximum pressure is reached.In another variation, the IOP mechanism is a pressure accumulator thatdampens the IOP within a specified range. Some variations of the IOPcontrol mechanism may include a pressure sensor. In yet anothervariation, the IOP control mechanism includes a slidable cap that coversthe dispensing member prior to its deployment, but which may slide orretract along the surface of the device housing to expose, deploy, oradvance the dispensing member e.g., upon attainment of a predeterminedIOP level. Sliding of the cap may be manually adjustable, e.g., using adial, or automatically adjustable, step-wise, or incremental in nature.For example, as shown in FIG. 40, integrated injection device (500)includes, among other elements, a cap (502), a stop (504), a trigger(506), a spring (508), a plunger (510), a seal (512), a drug reservoir(514), a needle (516), and a syringe (518). In use, when cap (502) isplaced against the ocular surface and pressure applied against theocular surface, cap (502) slidably retracts proximally (in the directionof the arrow) to stop (504) as the syringe (518) and needle (516) areadvanced. The trigger (506), e.g., a lever, may then be depressed torelease spring (508), which advances plunger (510) and seal (512) toinject drug from the drug reservoir (514) through needle (516). Once thedrug is injected, cap (502) slides back over the needle (516).

A locking mechanism may also be used to prevent sliding of the cap,cover or ocular contact surface, or prevent deployment of the dispensingmember until a predetermined IOP is reached. The locking mechanism mayalso be used to prevent sliding of the cap, cover, or ocular contactsurface if a predetermined IOP is not reached. For instance, the lockingmechanisms included on the devices described here that include aslidable cover, cap, etc., may be released manually or automaticallywhen the IOP reaches a predetermined level, such as between 20 mm Hg and80 mm Hg. Such locking mechanisms may include without limitation, hightraction surfaces, locking pins, interlocking raised ridges, or anyother type of locking mechanism that prevents the tip of the device,e.g., the cap or cover of the device, from sliding and thus exposing theneedle.

In yet further variations, the IOP control mechanism includes ahigh-traction surface or raised ridges on the cap, cover, or ocularcontact surface situated over the dispensing member. Such features maybe disposed on the inner surface of the cap, cover, or ocular contactsurface and configured so that upon sliding in the proximal direction,the high-traction surface or raised ridges mate with correspondingstructures (e.g., crimps, dimples, protrusions, other raised ridges) onthe surface of the device housing or other appropriate device componentto provide resistance of the cap, cover, or ocular contact surfaceagainst the eye wall (thus increasing ocular wall tension and IOP). Inthis instance, the IOP control mechanism comprises a dynamic resistancecomponent, as further described below. As stated above, the cap, cover,or ocular contact surface may be configured so that sliding is manuallyor automatically adjustable, step-wise, or incremental in nature. Whenraised ridges are employed, any suitable number may be used, and theymay be of any suitable size, shape, and geometry. For example, theraised ridges may be circumferentially disposed within the cap, cover,or ocular contact surface. In some instances, the raised ridges areconfigured with surfaces of differing slope. For example, the distalsurface may be configured to be steeper than the proximal surface. Withthis design, incremental sliding and incremental increases in IOP may begenerated when the cap, cover, or ocular contact surface is slidproximally, but sliding of the cap, cover, or ocular contact surfaceback over the dispensing member may also be accomplished due to thedecreased slope of the proximal ridge surface.

Dynamic Resistance Component

The application of pressure to the surface of the eye may beaccomplished and further refined by including a dynamic resistancecomponent to the injection device. The dynamic resistance component mayinclude a slidable element coupled to the housing. In some variations,the slidable element comprises a dynamic sleeve configured to adjust theamount of pressure applied to the eye surface, as further describedbelow. As previously stated, certain variations of the ocular walltension control mechanism function as dynamic resistance components.

The dynamic resistance component may also be configured as a dynamicsleeve. Similar to the slidable cap previously described, the dynamicsleeve may be configured to increase intraocular pressure and tension ofthe eye wall prior to needle injection. However, the dynamic sleeve iscapable of being manually manipulated to thereby adjust the amount ofpressure applied on surface of the eye (and thus, the amount of eye walltension). Having the ability to manually adjust the applied pressure mayallow the injector (user) to have improved control of the injection siteplacement and the injection angle, and also enhances the user's abilityto stably position the device on the ocular surface prior to needledeployment. In general, the dynamic sleeve is designed to enable theuser to precisely position the device tip at the targeted site on theeye surface and to firmly press the device tip against the eye wall toincrease wall tension and intraocular pressure. The dynamic sleeve maybe used to raise intraocular pressure to a predetermined level, asdescribed above, prior to the initiation of sleeve movement and needledeployment. It should be understood that the terms “dynamic sleeve,”“sleeve,” “dynamic sleeve resistance control mechanism,” and “sleeveresistance mechanism” are used interchangeably throughout. The dynamicsleeve will generally be configured such that when the user exerts apulling force (e.g., retraction) on the sleeve, this movement mayfacilitate needle exposure and reduce the amount of pressure force (downto 0 Newton) (“N” refers to the unit of force “Newton”) needed to beapplied to the eye wall in order to slide the sleeve back and expose theneedle. The dynamic sleeve may also be configured such that when theuser exerts a pushing force (e.g., advancement) on the sleeve, thismovement may counteract and impede needle exposure, which may allow thedevice tip to apply increased pressure to the eye wall prior to theinitiation of sleeve movement and needle exposure.

Some variations of the dynamic sleeve provide a variable force thatfollows a U-shaped curve, as described further in Example 1 and FIG. 46.Here the highest resistance is encountered at the beginning and the endof dynamic sleeve movement along the housing with decreased resistancebetween the start and end points of dynamic sleeve travel. In use, thistranslates to having an initial high-resistance phase (upon initialplacement on the eye wall) followed by a decrease in resistance tosleeve movement during needle advancement into the eye cavity. When theneedle is fully deployed, the dynamic sleeve will typically be at theend of its travel path, and increased resistance would again beencountered. This increase in resistive force allows the sleeve to cometo a smooth, gradual stop (instead of an abrupt hard stop at the endpoint) to minimize the risk of transmitting damaging amounts of force tothe inert eye wall (which in turn minimizes the risk of causingdiscomfort or injury to the eye). Here an exemplary dynamic sleeve maybe configured to be tapered at the proximal end and distal end.Referring to the sectional view in FIG. 42, integrated injection device(42) includes a housing (44), a resistance band (46) wholly or partiallysurrounding the housing, and a dynamic sleeve (48) that can be slidablyadvanced and retracted upon the housing (44). The dynamic sleeve (48)has a proximal end (50) and a distal end (not shown) that are tapered.The tapered ends may provide higher traction at the beginning and theend of the dynamic sleeve travel path along the device housing (44)(that is at the beginning and end of needle deployment). The taper atthe proximal end (50) provides higher traction and resistance at thebeginning of dynamic sleeve movement when it contacts resistance band(46). The thickness of the resistance band (46) may be varied to adjustthe amount of resistance desired. Upon reaching the wider middle segment(52), lower-traction and lower resistance movement is encountered,followed by higher traction and higher resistance at the end of needledeployment as the taper at the distal end of the dynamic sleeve isreached. As the dynamic sleeve becomes progressively more tapered at thedistal end, more traction is produced against the device housing untilit gradually comes to a complete stop. Instead of both ends beingtapered, in some variations one of the proximal end and distal end ofthe dynamic sleeve may be tapered.

Variable traction force may also be provided by components such ascircular raised bands or ridges on the outside surface of the devicetip. These components may provide counter-traction when approximatedagainst another circular raised band or ridge on the inside surface ofthe movable dynamic sleeve (inner bands or ridges). When the outer andinner bands or ridges are in contact with each other before the dynamicsleeve begins to move, they generate high traction and high resistanceto dynamic sleeve movement. Once the dynamic sleeve starts to move, theraised band on the outside of the device housing moves past the raisedband on the inside of the dynamic sleeve, which may result in a rapiddecrease in resistance to dynamic sleeve movement and, therefore,decreased pressure on the eye wall by the device tip. The shape of theraised interlocking bands or ridges will generally determine the shapeof resistance decrease. For example, the resistance decrease may followa sine-shaped profile.

In another variation, the dynamic sleeve may generate a force thatcontinuously decreases from its highest point before needle deployment(when the dynamic sleeve completely covers the needle), to its lowestpoint when the dynamic sleeve begins to move to expose the needle tip.Here the force remains low until the end of dynamic sleeve travel andcomplete needle deployment. This pattern of resistance decrease mayfollow a sine-shaped curve.

Slidable advancement of the dynamic sleeve may generate a force betweenitself and the housing ranging from 0 N to about 2 N. In some instances,slidable advancement of the dynamic sleeve generates a force betweenitself and the housing ranging from about 0.1 N to about 1 N.

Measuring Components

The devices described here may include a measuring component that may beuseful in determining the location of the intraocular injection site onthe eye surface. Integrated devices will generally include a measuringcomponent. The measuring component may be fixedly attached or removablyattached to the ocular contact surface. As previously stated, themeasuring component may be raised above the ocular surface so that itprevents the eye lid from coming in contact with the sterile ocularcontact surface of the device tip (e.g., FIGS. 2A-2B and 8). Thespecific configuration of the measuring component may also help tominimize the risk of inadvertent contamination of the sterile drugdispensing member (conduit) such as an injection needle. Suchcontamination may result from various causes such as the sterile needlecoming in inadvertent contact with an eyelid or other non-sterilesurface. The measuring components may also be colored in a manner toprovide color contrast against the surface of the eye including theconjunctiva, the sclera, and the iris.

In general, the measuring component will enable the intraocularinjection site to be more precisely placed at a specific distance from,and posterior or anterior to, the corneal-scleral junction termed “thelimbus.” In some variations, the measuring component may provide forplacement of the intraocular injection site from about 1 mm to about 5mm, from about 2 mm to about 4.5 mm, or from about 3 mm to about 4 mm,from and posterior to the limbus. In another variation, the measuringcomponent may provide for placement of the intraocular injection sitefrom about 2 mm to about 5 mm posterior to the limbus, or about 3.5 mmposterior to the limbus. In other variations, the measuring componentmay provide for placement of the intraocular injection site from withinabout 3 mm or about 2 mm, from and anterior to, the limbus, or betweenabout 0.1 mm and about 2 mm from and anterior to the limbus. In onevariation, the measuring component provides for placement of theintraocular injection site between about 1 mm anterior to the limbus andabout 6 mm posterior to the limbus. In another variation, the measuringcomponent provides for placement of the intraocular injection sitebetween about 3 mm to about 4 mm posterior to the limbus.

The measuring components may have any suitable configuration. Forexample, the measuring components may be located on one side of theocular contact surface or on more than one side of the ocular contactsurface (e.g., FIGS. 9, 10, and 11). Here, when the tip of the measuringcomponent is placed right next to the corneo-scleral limbus, the site ofthe intraocular needle injection is placed at a particular distance fromthe limbus, e.g., between about 3 mm and about 4 mm posterior to thelimbus.

In alternative variations, the measuring component comprises one or moremembers (e.g., FIGS. 9, 10, and 11). These members may radially extendfrom the ocular contact surface. Having more than one member comprisethe measuring component may be beneficial in ensuring that the distancebetween the limbus and injection site is measured perpendicular to thelimbus and not tangentially as it may be the case when the measuringmeans comprise a single member. When the tips of all members comprisingthe measuring component are aligned along the corneo-scleral limbus, thesite of the intraocular needle injection is placed at a particulardistance from the limbus, such as between about 3 mm and about 4 mmposterior to the limbus.

More specifically, as shown in FIG. 8, the device tip having an ocularcontact surface comprises a measuring component (80) that enables thedetermination of the injection site at a certain distance relative tothe corneo-scleral limbus. As previously stated, in one variation themeasuring component is located on one side of the device tip. In anothervariation, more than one measuring component is located on more than oneside of the device tip. In yet further variations, the tip of themeasuring component may be raised, bent, etc., which prevents the eyelid from sliding over the measuring component and coming in accidentalcontact with the dispensing member (conduit) of device. Also in FIG. 8,the dispensing member (conduit) is shown as being completely shieldedinside the device tip.

FIG. 9 provides further detail about another variation of the measuringcomponent. Here the device tip comprises a ring-shaped ocular contactsurface (90) and a measuring component (91) that enables thedetermination of the injection site at a certain distance relative tothe corneo-scleral limbus. The outer circumference of the device tipthat comes into contact with the surface of the eye has, e.g., a ringshaped ocular interface, and the dispensing member such as an injectionneedle may be hidden inside and protected by the device tip. In FIG. 9,the measuring components (91) are located on one side of the device tip(FIGS. 9A-9B) or on more than one side of the device tip (FIG. 9C).Thus, when the tip of the measuring component is placed next to thecorneo-scleral limbus, the site of intraocular needle injection isplaced at a specific distance from the limbus, such as between about 3mm and about 4 mm posterior to the limbus. Any suitable number ofmeasuring components may be provided on the device tip, e.g., attachedto the ocular contact surface. When a plurality of measuring componentsare used, they may be arranged around the ocular contact surface in anysuitable fashion. For example, they may be circumferentially disposedaround the ocular contact surface or on one side of the ocular contactsurface. They may be equally or unequally spaced around thecircumference of the ocular surface. In other variations, the measuringcomponents may be symmetrically spaced or asymmetrically spaced aroundthe circumference of the ocular contact surface. These configurationsmay be beneficial in allowing the injector to rotate the device alongits long axis.

FIGS. 10A-10C provide additional views of measuring components that aresimilar to those shown in FIGS. 9A-9C. In FIG. 10, a ring-shaped ocularcontact surface (93) is shown having a measuring component (93) thatenables the determination of the injection site at a certain distancerelative to and perpendicular to the corneo-scleral limbus (94). Themeasuring components are depicted on one side of the device tip, or inanother variation, on more than one side of the device tip. Again, themeasuring components may comprise one or more members. Having more thanone member comprise the measuring component may be beneficial inensuring that the distance between the limbus and injection site ismeasured perpendicular to the limbus and not tangentially as it may bethe case when the measuring component comprise a single member. When thetips of all members comprising the measuring component are aligned alongthe corneo-scleral limbus, the site of the intraocular needle injectionis placed at a particular distance from the limbus, such as betweenabout 3 mm and about 4 mm posterior to the limbus.

More than one measuring component is also shown in FIGS. 11A-11D. Herethe measuring components (95) are depicted as extending from a commonattachment point (96) on the ocular contact surface. When the tips ofall members comprising the said measuring component are aligned alongthe corneo-scleral limbus, the site of the intraocular needle injectionis placed at a particular distance from the limbus, such as betweenabout 3 mm and about 4 mm posterior to the limbus.

Alternatively, the measuring components may be configured as one or moreflexible measuring strips. Flexible materials that may be used to makethe measuring strips include flexible polymers such as silicones. Asshown in FIG. 44A, the measuring strip (800) may extend from the devicetip (802), usually from the side of the ocular contact surface (804), sothat the distance between the limbus and injection site can be measuredperpendicular to the limbus. A positional indicator component (806) maybe employed to ensure that the measuring strip (800) is properly used.For example, as shown in FIG. 44B, correct positioning of the measuringstrip (800) (so that a 90 degree angle is formed between the measuringstrip and device housing (808)) may be determined when the positionalindicator component is substantially taut. In contrast, a slackpositional indicator component (as shown in FIG. 44C) would indicateincorrect positioning. The positional indicator component may be a cord.In one variation, the integrated device comprises at least threemeasuring strips. In another variation, the integrated device includesat least four measuring strips. When a plurality of measuring strips areused, they may be configured in any suitable manner around the tip ofthe integrated device (equally spaced around the circumference of theocular contact surface, symmetric or asymmetrically placed around thecircumference of the ocular contact surface, etc.). For example, asshown in FIG. 44D, the measuring strips may be configured to span thedesired 90 degree angle (45 degrees plus 45 degrees between the fartheststrips) to allow for a 90 degree rotation of a control lever withouthaving to reposition the hand of the user.

In some variations, the measuring component may be configured as amarking tip member (97). As shown in FIG. 12, the marking tip member(97) at its distal end (closer to the eye) that interfaces with theocular surface and leaves a visible mark (98) on the conjunctivalsurface when pressed against it (e.g., FIG. 13). The marker-tip enablesintraocular injections to be carried out through a safe area of the eyerelative to the corneo-scleral limbus (99), such as between about 3 mmand about 4 mm posterior to the limbus, over the pars plana region ofthe ciliary body of the eye. The diameter of the marking tip may rangefrom about 1 mm to about 8 mm, or from about 2 mm to about 5 mm, or fromabout 2.3 mm to about 2.4 mm (e.g., FIG. 12).

Conduits

The intraocular drug delivery devices described here may include anysuitable conduit (or dispensing member) for accessing the intraocularspace and delivering active agents therein. The conduits may have anysuitable configuration, but will generally have a proximal end, a distalend, and a lumen extending therethrough. In their first, non-deployed(pre-deployed) state, the conduits will generally reside within thehousing. In their second, deployed state, i.e., after activation of theactuation mechanism, the conduit, or a portion thereof, will typicallyextend from the housing. By “proximal end” it is meant the end closestto the user's hand, and opposite the end near the eye, when the devicesare positioned against the eye surface.

The distal end of the conduit will generally be configured to be sharp,beveled, or otherwise capable of penetrating the eye surface, e.g., thesclera. The conduit employed may be of any suitable gauge, for example,about 25 gauge, about 26 gauge, about 27 gauge, about 28 gauge, about 29gauge, about 30 gauge, about 31 gauge, about 32 gauge, about 33 gauge,about 34 gauge, about 35 gauge, about 36 gauge, about 37 gauge, about 38gauge, or about 39 gauge. The wall of the conduit may also have anysuitable wall thickness. For example, in addition to regular wall (RW)thickness, the wall thickness of the conduit may be designated as thinwall (TW), extra/ultra thin wall (XTW/UTW), or extra-extra thin wall(XXTW). These designations are well known to those of skill in therelevant art. For example, the conduit may be a fine gauge cannula orneedle. In some variations, the conduits may have a gauge between about25 to about 39. In other variations, the conduits may have a gaugebetween about 27 to about 35. In yet further variations, the conduitsmay have a gauge between about 30 to about 33.

The conduits may have a sharp, pointed tip (FIGS. 14B-14C and FIGS.15A1-15A2), rather than a rounded one (FIG. 14A) as in conventionalneedles. The pointed needle tip is formed by the lateral side surfacesthat are straight at the point of their convergence into the tip, and atthe point of their convergence forming a bevel angle (the angle formedby the bevel and the shaft of the needle), which may range from betweenabout 5 degrees and about 45 degrees (FIG. 14B), between about 5 degreesand about 30 degrees, between about 13 degrees to about 20 degrees, orbetween about 10 degrees and about 23 degrees (FIG. 14C).

The sharp, pointed needle tip may provide improved penetration of theneedle through the fibrillar, fibrous scleral tissue, which is the majorstructural cover of the eye and consists of a network of strong collagenfibers. Thus, such a needle tip during its penetration through the eyewall may create less resistance and, thus, decrease the impact forcethat is transmitted to the intraocular structures, such as the retinaand the crystalline lens, in turn causing less damage to intraocularstructures during the intraocular injection process (compared toconventional needles).

In addition, such a narrow bevel angle may enable the needle to causeless sensation when it penetrates through the eye wall (the outer coverof the said eye wall being richly innervated with sensory nerve fibersendings particularly densely located in the conjunctiva and cornea),which may be an issue when intraocular injections are involved comparedto other less sensitive sites.

The narrow bevel angle may also allow for a longer bevel length andlarger bevel opening and, thus, a larger opening at the distal end ofthe injection needle. With such a configuration, the force of druginjection into an eye cavity may be reduced, thus reducing the chancesof intraocular tissue damage by a forceful stream of injected substance,which may occur with conventional short-beveled needles.

In some variations, the conduits are injection needles having one ormore flat surface planes, as well as one or more side-cutting surfaces,as illustrated in FIGS. 16 and 17. Examples include a needle shaftcomprising multiple surface planes separated by sharp ridges (FIGS.16A-16C), as well as a needle tip comprising sharp side-cutting surfaceslocated on either side of the beveled surface of the needle about 90degrees from the beveled surface (FIG. 17). The conduit may also bebi-beveled, i.e., have two bevels facing about 180 degrees from eachother that is located on the opposite sides of the conduit. The conduitmay also be coated (e.g., with silicone, PTFE, etc.) to facilitate itspenetration through the eye wall.

In other variations, the conduit may be configured to be wholly orpartially flattened in at least one dimension, as shown in thecross-sectional view of FIG. 18C taken along the line A-A of FIG. 18A.For example, the conduit may be flattened in the anterior-posteriordimension (that is from the beveled side of the needle towards itsopposite side. In one variation, both the external and internal surfacesof the needle are flattened and represent ovals on cross-section. Inanother variation, the internal surface of the needle is round andrepresents a circle on cross-section, while the external surface of theneedle is flattened to enable its easier penetration through the fibrousscleral or corneal tissue of the eye wall. In another variation, morethan one external surface plane of the needle is flattened to enable itseasier penetration through the fibrous eye wall, while the internalopening of the said needle may be of any shape including round or oval.

As previously stated, in its second, deployed state, the conduit orneedle extends from the housing. The portion of the needle that extendsfrom the housing can be referred to as the exposed needle length. Uponactivation of the actuation mechanism, the needle goes from its first,non-deployed state (pre-deployed state) (where it is entirely within thehousing of the device), to its second, deployed configuration outsidethe housing, where a certain length of it is exposed. This exposedlength may range from about 1 mm to about 25 mm, from about 2 mm toabout 15 mm, or from about 3.5 mm to about 10 mm. These exposed needlelengths may enable complete intraocular penetration through the sclera,choroid and ciliary body into the vitreous cavity, while minimizing therisk of intraocular damage. In some variations, the exposed needlelength ranges from about 1 mm to about 5 mm, or from about 1 mm to about4 mm, or from about 1 mm to about 3 mm. Here the exposed needle lengthsmay enable complete intraocular penetration through the cornea into theanterior chamber, while minimizing the risk of intraocular damage.

In some variations, the devices may include an exposure controlmechanism (9) for the dispensing member (11) (conduit) (FIGS. 19 and20). The exposure control mechanism (9) generally enables one to set themaximal length of the dispensing member exposure during dispensingmember deployment. In one variation, the exposure control mechanismworks by providing a back-stop for the needle-protective member (13). Inanother variation, the exposure control mechanism (9) may be a rotatingring member with a dialable gauge. Needle exposure could be adjusted bythe millimeter or a fraction of the millimeter, e.g., 1 mm, 1.5 mm, 2mm, 2.5 mm, 3 mm, etc. Here the device may be equipped with a retractionmechanism that controls needle retraction into a needle-protectivemember. Such a needle-retraction mechanism may be spring-actuated (FIG.20).

The devices may also include a removable distal (towards the eye) memberthat covers and protects the conduit (e.g., the front cover (15) in FIG.21). In one variation, the devices may also include a removable proximal(away the eye) member that covers and protects the proximal part of thedevice, e.g., comprising a loading dock mechanism (17) (e.g., the backcover (19) in FIG. 21).

Reservoirs

The reservoir is generally contained within the housing and may beconfigured in any suitable manner, so long as it is capable ofdelivering an active agent to the intraocular space using the actuationmechanisms described herein. The reservoir may hold any suitable drug orformulation, or combination of drugs or formulations to the intraocularspace, e.g., the intravitreal space. It should be understood that theterms “drug” and “agent” are used interchangeably herein throughout. Inone variation, the drug reservoir is silicone oil-free (lacks siliconeoil or one of its derivatives) and is not internally covered orlubricated with silicone oil, its derivative or a modification thereof,which ensures that silicone oil does not get inside the eye causingfloaters or intraocular pressure elevation. In another variation, thedrug reservoir is free of any lubricant or sealant and is not internallycovered or lubricated with any lubricating or sealing substance, whichensures that the said lubricating or sealing substance does not getinside the eye causing floaters or intraocular pressure elevation.

In some variation, the reservoir is made of a material that contains acyclic olefin series resin, a cyclic olefin ethylene copolymer includingcommercially available products such as Zeonex® cyclo olefin polymer(ZEON Corporation, Tokyo, Japan) or Crystal Zenith® olefinic polymer(Dalkyo Seiko, Ltd., Tokyo, Japan) and APEL™ cyclo olefin copolymer(COC) (Mitsui Chemicals, Inc., Tokyo, Japan), a cyclic olefin ethylenecopolymer, a polyethylene terephthalate series resin, a polystyreneresin, a polybutylene terephthalate resin, and combinations thereof. Inone variation, it may be beneficial to use a cyclic olefin series resinand a cyclic olefin ethylene copolymer that have a high transparency, ahigh heat resistance, and minimal to no chemical interaction with apharmacological product such as a protein, a protein fragment, apolypeptide, or a chimeric molecule including an antibody, a receptor ora binding protein.

Exemplary agents may be selected from classes such asanti-inflammatories (e.g., steroidal and non-steroidal), anti-infectives(e.g., antibiotics, antifungals, antiparasitics, antivirals, andantiseptics), cholinergic antagonists and agonists, adrenergicantagonists and agonists, anti-glaucoma agents, neuroprotection agents,agents for cataract prevention or treatment, anti-oxidants,antihistamines, anti-platelet agents, anticoagulants, antithrombics,anti-scarring agents, anti-proliferatives, anti-tumor agents, complementinhibitors (e.g., anti-C5 agents, including anti-C5a and anti-C5bagents), vitamins (e.g., vitamin B and derivatives thereof, vitamin A,depaxapenthenol, and retinoic acid), growth factors, agents to inhibitgrowth factors, gene therapy vectors, chemotherapy agents, proteinkinase inhibitors, tyrosine kinase inhibitors, PEGF (pigment epithelialgrowth factor), small interfering RNAs, their analogs, derivatives,conjugates, and modifications thereof, and combinations thereof.

Non-limiting, specific examples of drugs that may be used alone or aspart of a combination drug therapy include Lucentis™ (ranibizumab),Avastin™ (bevacizumab), Macugen™ (pegaptanib), steroids, e.g.,dexamethasone, dexamethasone sodium phosphate, triamcinolone,triamcinolone acetonide, and fluocinolone, taxol-like drugs, integrin oranti-integrin agents, vascular endothelial growth factor (VEGF) trap(aflibercept), anecortave acetate (Retaane), and limus family compounds.Non-limiting examples of members of the limus family of compoundsinclude sirolimus (rapamycin) and its water soluble analog SDZ-RAD,tacrolimus, everolimus, pimecrolimus, and zotarolimus, as well asanalogs, derivatives, conjugates, salts, and modifications thereof, andcombinations thereof.

Topical anesthetic agents may also be included in the reservoirs. Forexample, lidocaine, proparacaine, prilocalne, tetracaine, betacaine,benzocaine, ELA-Max®, EMLA® (eutectic mixture of local anesthetics), andcombinations thereof may be used.

The reservoirs and devices described here may be suitable forintraocular administration of a very small volume of a solution,suspension, gel or semi-solid substance. For example, a volume betweenabout 1 μl and about 200 μl, or between about 10 μl and about 150 μl, orbetween about 20 μl and about 100 μl may be delivered. To that end, thedevice will generally have a very small “dead space,” which enablesintraocular administration of very small volumes.

The device reservoirs may be pre-loaded during the manufacturing processor loaded manually before the intraocular injection, as furtherdescribed below.

Drug Loaders

When a drug or formulation is to be loaded into the reservoir of thedevice prior to intraocular injection, a loading member may be employed.The loading member may be removably attached to the distal end of thehousing. For example, the loading member may function as a loading dockthat quantitatively controls the volume of a liquid, semi-liquid,gelatinous, or suspension drug that is to be loaded into the device. Forexample, the loading member may comprise a dial mechanism (21) thatallows the operator to preset a particular volume of a drug to be loadedinto the device (FIGS. 21 and 22). The loading may occur with aprecision raging from about 0.01 μl and about 100 μl, or from about 0.1μl and 10 μl. Such a loading member may allow for loading the devicereservoir with a liquid, semi-liquid, gelatinous or suspended drug in aparticular volume equal or less than that of the drug storage container,which allows for airless loading of the drug into the device. This maybe beneficial because air injected into the eye will result in thesensation of seeing “floaters” by the patient, which may beuncomfortable and distracting to the patient particularly during drivingor other similar activities.

As shown in FIG. 22, the drug loading mechanism (23) includes a widebase member (25) for upright loading of the reservoir (27) through itsproximal (further from the eye) end (29). Also shown are exemplary front(31) and back (33) covers, as well as a dialable control mechanism (21)for setting the loading and/or injection volume(s). In other variations,the devices comprise a loading mechanism such as a loading dock (35A),wherein the dock (35A) interfaces with a drug storage container (FIGS.25A-25B) such as a vial known to those skilled in the art and penetratesthrough the vial stopper to gain access to the drug contained inside thevial so that the drug could be loaded into the device reservoir. InFIGS. 25A-25B, the dock mechanism is located in the dependant positionso that the drug vial (37) is positioned directly above the dock so thatthe drug moves from the vial downward in the direction of gravity.

In one variation, the dock mechanism comprises a needle or a sharpcannula that has openings or fenestrations (39) at its base. The saidopenings or fenestrations are positioned immediately adjacent to theinternal aspect of the vial stopper when the loading dock penetratesinto the drug vial while in the desired loading position, which in turnenables airless drug loading into the device as well as complete drugremoval from the storage container. Airless drug loading may bebeneficial because it may prevent the patient from seeing smallintraocular air bubbles or “floaters.” Complete drug removal is alsobeneficial given that small drug volumes and expensive medications aretypically used.

In other variations, for example, when the devices have a flat sidesurface (FIGS. 24A-24D) or a flat front or back surface (FIG. 22), theloading mechanism includes a loading dock located 180 degrees from theflat surface. This results in a loading dock pointing straight upwards,which enables its penetration into a drug container in the dependentposition, which in turn enables airless drug delivery into the device,as well as complete drug removal from the storage container and itsloading into the said device without drug retention and loss in thestorage container.

In further variations, as shown in FIGS. 33A-33B, an access port (144)may be provided at the distal end of the needle assembly (125) thatallows drug from a storage container (146) to be loaded into thereservoir (122). Access port (144) may be placed at any suitablelocation on the needle assembly (125) or housing (102). For example, ifdesired, the access port may be placed in the front wall of the housingor even the ocular contact surface (not shown) so that drug loadingoccurs from the front of the device. Access port (144) may be made froma material, e.g., silicone, that allows sealable penetration by a sharpconduit. One or multiple membranes (148) may also be provided, e.g., inthe ocular contact surface (108) to seal the internal compartment of thehousing against air leak and/or external bacterial contamination. One ormultiple small apertures (150) may also be included in the wall of thehousing (102) to help control air outflow from the housing (102). Thenumber and diameter of the apertures (150) may be varied to control therate of (needle assembly and) needle deployment.

In some variations, e.g., when a pneumatic actuation mechanism is used,drug loading may be controlled by a drug-loading piston. For example, asshown in FIG. 38, the device (400) may include a drug-loading piston(402) having a proximal end (404) and a distal end (406). The distal end(406) is adapted to include a threaded portion (408). Thus, duringloading of a drug from container (410) through adaptor (412) and accessport (414), the drug-loading piston (402) can be rotated and withdrawnto create negative pressure within the reservoir (416). This negativepressure in turn draws the drug through the needle (418) and into thereservoir (416). A receptacle (420) may also be provided at the distalend of the device for holding initially loaded drug prior to transferinto the reservoir (416).

Actuation Mechanisms

The devices described here generally include an actuation mechanismwithin the housing that deploys the conduit from the housing and enablesthe delivery of drug from the device into the intraocular space. Inother variations, the conduit is deployed by an actuation mechanismcontained within a separate cartridge that can be removably attached tothe device housing, e.g., using snap-fit or other interlocking elements.The actuation mechanisms may have any suitable configuration, so long asthey provide for accurate, atraumatic, and controlled delivery of druginto the intraocular space. For example, the actuation mechanisms maydeliver a drug or formulation into the eye by way of intraocularinjection at a rate ranging from about 1 μl/sec to about 1 ml/sec, fromabout 5 μl/sec to about 200 μl/sec, or from about 10 μl/sec to about 100μl/sec. The actuation mechanisms may generally provide a force of needledeployment that is strong enough to penetrate the eye wall comprisingthe conjunctiva, sclera and the pars plana region of the ciliary body,but less than that causing damage to the intraocular structures due tohigh velocity impact. This force depends on several physical factors,including but not limited to, the needle gauge utilized, the speed/rateof needle deployment at the point of contact between the needle tip andthe eye wall which in turn determines the impact force. An exemplaryrange of force that may be generated by the actuation mechanisms isabout 0.1 N (Newton) to about 1.0 N (Newton). The velocity of needledeployment may also range between about 0.05 seconds and about 5seconds.

In some variations, the actuation mechanism is a single-springmechanism. In other variations, the actuation mechanism is a two-springmechanism. In further variations, the actuation mechanism is pneumatic,e.g., employing negative pressure such as vacuum, or a positive pressuredriven mechanism. In further variations, the actuation mechanism isdriven magnetically or electrically, e.g., by a piezo-electric ormagnetic rail mechanism. These types of actuation mechanisms may beconfigured to allow independent control of the rate and force of druginjection (controlled, e.g., by the first spring member in thetwo-spring variation), and the rate and force of the dispensing memberdeployment (controlled, e.g., by the second spring member in thetwo-spring variation). Exemplary two-spring mechanisms are shown inFIGS. 26 and 27.

FIG. 28 also depicts an exemplary integrated intraocular drug deliverydevice with a two-spring actuation mechanism. In FIG. 28, the device(100) includes a housing (102) having a proximal end (104) and a distalend (106). An ocular contact surface (108) is attached to the distal end(106). A measuring component (110) is attached to one side of the ocularcontact surface (108). As further described below, a trigger (112) thatis operatively coupled to the housing (102) works with the first spring(114) and the second spring (116) of the actuation mechanism to deploypins (118) through openings (120) in the housing (102), to therebydeliver drug from the reservoir (122). First spring (114), second spring(116), pins (118), openings (120), and reservoir (122) are better shownin FIG. 29. Also in FIG. 29, a conduit, e.g., needle (124), is depictedwithin the housing in its first non-deployed state. Needle (124) isconfigured as being part of an assembly (125) such that movement of theassembly results in corresponding movement of the needle (124). A stop(115) is provided at the proximal end (127) of the assembly (125), whichis connected to the distal end of the first spring (114) and theproximal end of the second spring (116). The springs, as well as othercomponents of the device may be connected via medical grade adhesives,friction or snap fit, etc.

In FIG. 30, the second spring (116) is operatively connected to aplunger (132) by friction fit within a compartment (134) of the plunger(132). In the pre-activated state, as shown in FIG. 29, the plunger(132) and second spring (116) are held in place by pins (118). The pins(118) are removably engaged to the plunger (132) at plunger groove(138), and lock the plunger (132) in place via friction fit against theplunger groove (138) and housing (102).

Activation of the first spring (114) of the actuation mechanism byactivating the trigger deploys the needle (124) into the intraocularspace, i.e., it moves the needle (124) from its first non-deployed state(FIG. 29) to its second deployed state (FIG. 30). Referring to FIGS. 30and 31A-31C, activation of the first spring (114) occurs by depressionof trigger (112) by, e.g., one or two fingers, which also depressesbuttons (126). As shown in FIGS. 31A and 31B, buttons (126) areconfigured with a button groove (128) that allows the buttons (126) toalign with channels (130) in the housing (102). Once aligned with thechannels (130), the buttons (126) may be slidingly advanced along thechannels (130). The rate of movement along the channels (130) may becontrolled manually by the user, automatically controlled by the forceof spring expansion, or a combination of both. This movement of thebuttons (126) allows expansion of the first spring (114) against stop(115) so that the needle assembly (125) and needle (124) can bedeployed. The channels in the housing may have any suitableconfiguration. For example, as shown in FIG. 31C, the channels (130) maybe spiral cut within the housing to allow rotation or a corkscrew typemovement of the needle upon advancement, which may facilitate needlepenetration through the eye wall.

Activation of the first spring (114) will typically result in activationof the second spring (116) to deliver drug out of the device and intothe intraocular space. For example, as shown in FIG. 30, the expansionforce of first spring (114) against stop (115) that is also connected tothe proximal end of the second spring (116) works to expand the secondspring (116) so that the assembly (125) is advanced within the housing(102). As illustrated in FIGS. 32A-32C, when the pins (118) that areremovably engaged to plunger (132) reach openings (120), they aredeployed out through the openings (120). Expulsion of the pins (118)from the device, then allows free expansion of the second spring (116)against plunger (132), to thereby push drug residing with reservoir(122) out of the device. The openings (120) may be covered by a membraneor seal (140) that can be penetrated by the pins (118) to give a visualindication that the drug has been delivered.

A two-spring actuation mechanism, as shown in FIGS. 41A-41B may also beused. Referring to FIG. 41A, integrated device (600) includes anactuation mechanism comprising a first spring (602) and a second spring(604). In use, when trigger (606), e.g., a lever, is depressed, firstspring (602) is released to advance shaft (608) in the direction of thearrow, which in turn advances needle (610) out of the tip of the device(600). Continued advancement of the shaft (608) advances the injectionsleeve (612) and top seal (614) so that drug within reservoir (616) maybe delivered through needle (610). Referring to FIG. 41B, once the drughas been injected, tabs (618) removably engage housing openings (620) tothereby release second spring (604), which then moves shaft (608)backward to retract needle (610) (not shown).

In some variations, a single-spring actuation mechanism is employed, asshown in FIGS. 36 and 37. When a single spring is used, the actuationmechanism is configured much like the two-spring mechanism describedabove except that the second spring is removed. Thus, in itspre-activated state, as shown in FIG. 36, a device (300) with a singlespring (302) may activate the single spring (302) by depression oftrigger (304) by, e.g., one or two fingers, which also depresses buttons(306). The buttons (306) are configured with a button groove (308) thatallows the buttons (306) to align with channels (not shown) in thehousing (310). Once aligned with the channels, the buttons (306) may beslidingly advanced along the channels. This movement of the buttons(306) allows expansion of the spring (302) against plunger (312) so thatthe needle assembly (314) and needle (316) can be deployed. When thepins (318) that are removably engaged to plunger (312) reach openings(320) within the housing (310), they are deployed out through theopenings (320). Expulsion of the pins (318) from the device, then allowsfurther expansion of the spring (302) against plunger (312), to therebypush drug residing with reservoir (322) out of the device. Although notshown here, the openings (320) may be covered by a membrane or seal thatcan be penetrated by the pins (318) to give a visual indication that thedrug has been delivered.

A pneumatic actuation mechanism may also be employed. In one variation,as depicted in FIGS. 34 and 35A and 35B, the pneumatic actuationmechanism includes a plunger, pins, and housing openings in the samefashion as described for the single- and two-spring mechanisms. However,instead of using a spring to deploy the needle assembly and plunger, apiston is used to slidingly advance the needle assembly within thehousing. For example, in FIG. 34, a device with a pneumatic actuationmechanism (200) includes a piston (202) and trigger (204). The piston(202) is used to compress air into the housing (206) of the device(202). If desired, the amount of compressed air the piston includes inthe device may be controlled by a dial or other mechanism (not shown).The proximal end of the housing may also be configured, e.g., with aflange, crimps, or other containment structure, that allowstranslational movement of the piston (202) into the housing but not outof the housing. Upon depression of a trigger (208), a pair of lockingpins (210) are also depressed to thereby allow the compressed airgenerated by the piston (202) to push the needle assembly (212) forward.This advancement of the needle assembly (212) deploys the needle (214)out of the device (FIG. 35B). As previously stated, pins (216) similarto those above that lock the plunger (218) in place are also provided.Upon their expulsion from the device out of openings (220) in thehousing (206) due to forward movement of the needle assembly (212), thecompressed air further moves the plunger (218) forward to thereby pushdrug residing with reservoir (222) out of the device. Rotational pins(224) may also be included, which upon release by the sliding needleassembly (212) allow rotation of the needle assembly (212) with respectto the housing (206).

As previously stated, a trigger may be coupled to the housing andconfigured to activate the actuation mechanism. In one variation, thetrigger is located on the side of the device housing proximate thedevice tip at the ocular interface surface (e.g., the distance betweenthe trigger and device tip may range between 5 mm to 50 mm, between 10mm to 25 mm, or between 15 mm to 20 mm), so that the trigger can beactivated by a fingertip while the device is positioned over the desiredocular surface site with the fingers on the same hand. In anothervariation, the trigger is located on the side of the device housing at90 degrees to the measuring component, so that when the ocular contactsurface is placed on the eye surface perpendicular to the limbus, thetrigger can be activated with the tip of the second or third finger ofthe same hand that positions the device on the ocular surface.

Some variations of the device may include a control lever for initiatingplunger movement. In these instances, the control lever may actuate theplunger in a mechanical manner, e.g., by spring-actuation, similar tothat described above. In other variations, actuation of the plunger mayoccur through a combination of mechanical and manual features. Forexample, the initiation of plunger movement may be aided by a manualforce applied onto the control lever, while a spring-actuated mechanismfor generating a mechanical force is also employed to move the plungerforward inside the device barrel to inject drug. In instances where thecontrol lever is connected to the plunger, the initiation of plungermovement and drug injection is controlled by the manual component,whereas the rate of fluid injection is controlled by the mechanicalforce. Here a reduced manual force may be applied to the plunger due toits combination with a co-directional mechanical force, thusfacilitating the stability of device positioning on the ocular surfaceat a precise injection site.

The control lever may be placed between 10 mm and 50 mm from the tip ofthe device that interfaces with the eye surface, or between 20 mm and 40mm from the tip of the device. Positioning of the control lever in thismanner may enable atraumatic and precise operation of the device withone hand.

As illustrated in FIGS. 43A-43D, exemplary integrated device (700)includes a housing (702), a dynamic sleeve (704) slidable thereon, anocular contact surface (706), a plunger (708), and a control lever (710)for manually actuating the plunger (708) to inject drug through needle(712). An expanded sectional view of the ocular contact surface (706),dynamic sleeve (706), plunger (708), and needle (712) shown in FIG. 43 Ais shown in FIG. 43B. In use, after placing the ocular contact surface(706) on the eye, the applied pressure may automatically slide thedynamic sleeve (704) back (in the direction of the arrow) to expose theneedle and allow needle penetration through the eye wall. The controllever (710) may then be slidably advanced manually (in the direction ofthe arrow in FIG. 43C) to advance plunger (708). When injection of thedrug through the needle (712) is complete, the dynamic sleeve (704) maybe slidably advanced manually to cover the needle, as shown in FIG. 43D.

The dynamic sleeve may be slidably advanced or retracted manually by afine mobility control mechanism, also referred to as a mobility controlmechanism. In these instances, the dynamic sleeve may comprise ahigh-traction surface located on the outer surface of the sleeve, whichmay aid movement of the sleeve with a fingertip. In one variation, thehigh-traction surface may be engraved or contain markings with aserrated pattern. In other variations, as shown in FIG. 45A, a platformor pad (e.g., a fingertip pad) (900) may be attached to the outersurface of the sleeve (902) to help manually advance or retract thesleeve. The platform or pad may also include a high-traction surface(904), the perspective, side, and top views of which are illustrated inFIGS. 45B, 45C, and 45D, respectively. Platform or pad (900) willtypically include a base (912) for attachment to the sleeve (902). Base(912) may be of any suitable configuration. For example, the base of theplatform or pad may be configured as a cylinder (FIG. 45H) or with anarrowed portion (portion of lesser diameter), such as a dumbbell orapple core shape (FIG. 45I).

Some variations of the devices described herein include a grip having aretraction slot or channel that works in combination with the dynamicresistance component to inject drug into the eye. Referring to FIG. 45A, grip (906) may be a component coupled (usually fixedly attached) tothe device housing (908) at the proximal end (912) of the sleeve (902).The grip (906) may be configured to include a retraction slot (910) inits wall. In use, when the sleeve (902) is retracted, as shown by thedirection of the arrow in FIG. 45J, the base (912) of the pad orplatform is moved into the slot (910). The retraction slot (910) may beconfigured as a channel of uniform width (FIG. 45F), or as a channelwith a keyhole-type configuration, e.g., having a narrowed portion (FIG.45G) or enlarged portion (FIG. 45E) at the slot proximal or distal end.The retraction slot may provide sensory feedback, e.g., when theendpoint of retraction is reached. The configuration of the base of theplatform or pad may be chosen so that it provides a friction fit withthe slot. For example, when the slot has a narrowed portion, the basemay also have a narrowed portion.

When grips are employed, the devices may also include a lockingmechanism. In one variation, when the end point of the sleeve retractionand needle exposure/deployment is reached, the wide portion of thesleeve slot is aligned with the wide portion of a grip slot and with anopening in the housing and an opening in the plunger shaft, allowing theplatform base to be inserted into the plunger shaft to lock it relativeto the platform that become an actuation lever for manual druginjection. The narrow part of the base enters the narrow part of thesleeve slot, which unlocks the platform relative to the sleeve allowingits movement towards device tip. In another variation, when the platformbase reaches the end point of the retraction slot, it may be depressedinto an opening in the plunger shaft and becomes a locking pin toconnect the platform and the plunger. When it is depressed, its narrowportion enters the keyhole-shaped slot in the sleeve, and becomesmovable within the slot moving towards the tip of the sleeve (unlocksthe platform base and sleeve).

The mobility control mechanism may be beneficial when the user desiresto control the amount of pressure exerted by the device tip on the eyesurface in order to deploy the needle during its intraocularpenetration. With a mobility control mechanism, the user may use afingertip to either reduce or increase counter-forces that regulate thesleeve movement and needle exposure.

For example, if the user exerts the pulling force onto the saidhigh-traction surface (that is pulling the high-traction surface of thesleeve away from the device tip), this movement may facilitate needleexposure and reduce the amount of pressure force (down to 0 Newton)needed to be applied to the eye wall in order to slide the sleeve backand expose the needle. In another variation, if the user exerts apushing force (that is pushing the high-traction surface of the sleevetowards the device tip), this movement may counteract and impedes needleexposure, which may allow the device tip to apply increased pressure tothe eye wall prior to the initiation of sleeve movement and needleexposure.

In use, the platform or pad may be slid with a second or third finger.Again, this allows the injector to manually modulate the sleeveresistance and movement along the device tip. For example, by pushingthe pad and thus the sleeve forward with a fingertip, the injectorprovides some resistance at the beginning of the procedure when thedevice tip is being positioned on the eye surface (and the needle needsto remain completely covered). Then the injector would release his/herfingertip from the sleeve pad to enable needle deployment and itstransscleral penetration. Some variations of the device may also includea step or a ring-shaped ridge at the end of the sleeve path, so thatafter the sleeve is pulled back past this step, it would automaticallytrigger spring-actuated plunger movement. The fingertip pad could beused to pull the sleeve back past the said step at the end of needledeployment in order to actuate the plunger movement and drug injection.

When a platform or pad is employed, it may reduce the amount of pressurethe device exerts on the eyeball before the sleeve begins to move toexpose the needle, and thus, allow customization of the amount ofapplied pressure from patient to patient.

In another aspect, the dynamic sleeve may provide gradual needleexposure as it penetrates through the eye wall so that the needle isexposed 1 mm or less when it meets most resistance at the eye surface.Here the rest of the needle is located inside the sleeve with at leastits most distal unexposed point or a longer segment being protectedinside the narrow exit orifice or canal. Such sleeve design may minimizethe risk of needle bending compared to the conventional syringe with along exposed needle. This design may enable the utilization of smaller agauge needle without increased risk of it being bent as it penetratedthrough the eye wall. The smaller needle gauge may render it morecomfortable and less traumatic during its intraocular penetration.

II. METHODS

Methods for using the integrated intraocular drug delivery devices arealso described herein. In general, the methods include the steps ofpositioning an ocular contact surface of the device on the surface of aneye, applying pressure against the surface of the eye at a targetinjection site using the ocular contact surface, and delivering anactive agent from the reservoir of the device into the eye by activatingan actuation mechanism. The steps of positioning, applying, anddelivering are typically completed with one hand.

The application of pressure against the surface of the eye using theocular contact surface may also be used to generate an intraocularpressure ranging between 15 mm Hg to 120 mm Hg, between 20 mm Hg to 90mm Hg, or between 25 mm Hg to 60 mm Hg. As previously stated, thegeneration of intraocular pressure before deployment of the dispensingmember (conduit) may reduce scleral pliability, which in turn mayfacilitate the penetration of the conduit through the sclera, decreaseany unpleasant sensation on the eye surface during an injectionprocedure, and/or prevent backlash of the device. Intraocular pressurecontrol may be generated or maintained manually or automatically usingpressure relief valves, pressure sensors, pressure accumulators,pressure sensors, or components such as slidable caps having lockingmechanisms and/or ridges as previously described.

Use of the devices according to the described methods may reduce painassociated with needle penetration through the various covers of the eyewall such as the conjunctiva that is richly innervated with pain nerveendings. The anesthetic effect at the injection site during anintraocular injection procedure may be provided by applying mechanicalpressure on the conjunctiva and the eye wall over the injection sitebefore and/or during the needle injection. The application of mechanicalpressure to the eye wall may also transiently increase intraocularpressure and increase firmness of the eye wall (and decrease itselasticity), thereby facilitating needle penetration through the sclera.Furthermore, the application of mechanical pressure to the eye wall maydisplace intraocular fluid within the eye to create a potential spacefor the drug injected by the device.

The devices may be used to treat any suitable ocular condition.Exemplary ocular conditions include without limitation, any type ofretinal or macular edema as well as diseases associated with retinal ormacular edema, e.g., age-related macular degeneration, diabetic macularedema, cystoid macular edema, and post-operative macular edema; retinalvascular occlusive diseases such as CRVO (central retinal veinocclusion), BRVO (branch retinal vein occlusion), CRAO (central retinalartery occlusion), BRAO (branch retinal artery occlusion), and ROP(retinopathy of prematurity), neovascular glaucoma; uveitis; centralserous chorioretinopathy; and diabetic retinopathy.

When dexamethasone sodium phosphate solution is used to treat an ocularcondition, the dose of dexamethasone sodium phosphate that may beadministered into the eye by each individual injection device may rangebetween about 0.05 mg and about 5.0 mg, between about 0.1 mg and about2.0 mg, or between about 0.4 mg and about 1.2 mg.

In some variations, a topical anesthetic agent is applied on the ocularsurface before placement of the device on the eye. Any suitable topicalanesthetic agent may be used. Exemplary topical anesthetic agentsinclude without limitation, lidocaine, proparacaine, prilocalne,tetracaine, betacaine, benzocaine, bupivacaine, ELA-Max®, EMLA®(eutectic mixture of local anesthetics), and combinations thereof. Inone variation, the topical anesthetic agent comprises lidocaine. Whenlidocaine is used, it may be provided in a concentration raging fromabout 1% to about 10%, from about 1.5% to about 7%, or from about 2% toabout 5%. In another variation, the topical anesthetic agent is mixedwith phenylephrine or another agent that potentiates or/and prolongs theanesthetic effect of the pharmaceutical formulation. The topicalanesthetic agent may be provided in any suitable form. For example, itmay be provided as a solution, gel, ointment, etc.

An antiseptic agent may also be applied on the ocular surface beforeplacement of the device on the eye. Examples of suitable antisepticagents include, but are not limited to, iodine, povidone-iodine(Betadine®), chlorhexidine, soap, antibiotics, salts and derivativesthereof, and combinations thereof. The antiseptic agent may or may notbe applied in combination with a topical anesthetic agent. When theantiseptic comprises povidone-iodine (Betadine®), the concentration ofpovidone-iodine may range from about 1% to about 10%, from about 2.5% toabout 7.5%, or from about 4% to about 6%.

During the drug delivery process, the devices described here may beconfigured so that the injection needle enters the eye at the rightangle that is perpendicular to the eye wall (sclera). In otherinstances, the device may be configured so that the injection needleenters through the cornea into the anterior chamber of the eye parallelto the iris plane.

III. SYSTEMS AND KITS

Systems and kits that include the intraocular drug delivery devices arealso described herein. The kits may include one or more integrated drugdelivery devices. Such devices may be preloaded with an active agent.When a plurality of preloaded devices are included, they may beseparately packaged and contain the same active agent or differentactive agents, and contain the same dose or different doses of theactive agent.

The systems and kits may also include one or more separately packageddevices that are to be manually loaded. If the devices are to bemanually loaded prior to use, then one or more separately packagedactive agents may be incorporated into the kit. Similar to the preloadeddevice system or kit, the separately packaged active agents in thesystems and kits here may be the same or different, and the doseprovided by each separately packaged active agent may be the same ordifferent.

Of course, the systems and kits may include any combination of preloadeddevices, devices for manual loading, and active agents. It should alsobe understood that instructions for use of the devices will also beincluded. In some variations, one or more separately packaged measuringcomponents may be provided in the systems and kits for removableattachment to the devices. Topical anesthetic agents and/or antisepticagents may also be included.

IV. EXAMPLES

The following example serves to more fully describe the manner of usingthe above-described intraocular injection devices. It is understood thatthis example in no way serves to limit the scope of the invention, butrather is presented for illustrative purposes.

Example 1 Resistance Force Generated by the Dynamic Sleeve

An intraocular injection device comprising a 30-gauge needle covered bya dynamic sleeve (a bi-tapered design with each end of the sleevetapered) was fixed onto an Imada tensile testing bed and moved againstan Imada 10 N force gauge at a rate of 10 mm/minute. The resistanceforce was measured while the sleeve was pushed back to expose the needlesimulating the movement of the sleeve in practice. This produced a“U”-shaped force plotted against the sleeve displacement curve, as shownin FIG. 46. The resistance force at the beginning and the end of sleevemovement path was greater than that in the middle of the path. In FIG.46, the illustrated range of resistance force generated may be betweenzero Newton and about 2 Newton or between about 0.1 Newton and about 1.0Newton.

In one instance, the resistance force at the beginning of the sleevepath equaled the force required for the 30- or 31-gauge needle topenetrate through the human sclera (e.g., between 0.2 Newton and 0.5Newton). When a using a higher-resistance sleeve was employed, theresistance force at the beginning of the sleeve path was greater thanthe force required for the 30- or 31-gauge needle to penetrate throughthe human sclera (e.g., over 1 Newton). However, the force was lowenough to be comfortable for the patient and avoid potential damage tothe eye (e.g., to avoid increase in intra-ocular pressure over 60 mmHg).In the middle portion of the sleeve movement path, the force approachedzero Newton.

1. An integrated device for intraocular drug delivery comprising: ahousing sized and shaped for manipulation with one hand, the housinghaving a proximal end and a distal end; an ocular contact surface at thehousing distal end; a measuring component; a conduit at least partiallywithin the housing, the conduit having a proximal end, a distal end, anda lumen extending therethrough; an actuation mechanism contained withinthe housing and operably connected to the conduit and a reservoir forholding an active agent; a trigger coupled to the housing and configuredto activate the actuation mechanism; and a dynamic resistance componentcoupled to the housing.
 2. The integrated device of claim 1, wherein thedynamic resistance component comprises a slidable element coupled to thehousing.
 3. The integrated device of claim 2, wherein the slidableelement comprises a dynamic sleeve having a proximal end, a distal end,and an inner surface.
 4. The integrated device of claim 3, wherein theproximal end and the distal end of the dynamic sleeve are tapered. 5.The integrated device of claim 4, wherein the tapered dynamic sleeve andthe housing generate a force between 0 N and about 2 N.
 6. Theintegrated device of claim 4, wherein the tapered dynamic sleeve and thehousing generate a force between about 0.1 N and about 1 N.
 7. Theintegrated device of claim 3, wherein the inner surface of the dynamicsleeve comprises one or more high-traction surfaces.
 8. The integrateddevice of claim 7, wherein the housing comprises one or morehigh-traction surfaces.
 9. The integrated device of claim 8, wherein theone or more high-traction surfaces of the dynamic sleeve and the housinggenerate a force between 0 N and about 2 N.
 10. The integrated device ofclaim 8, wherein the one or more high-traction surfaces of the dynamicsleeve and the housing generate a force between about 0.1 N and about1.0 N.
 11. The integrated device of claim 3, wherein the dynamic sleevefurther comprises a fine sleeve mobility control component.
 12. Theintegrated device of claim 1, wherein the ocular contact surfacecomprises a ring, a flange, or a combination thereof.
 13. The integrateddevice of claim 12, wherein the ocular contact surface comprises a ring.14. The integrated device of claim 13, wherein the ring has a diameterbetween about 0.3 mm and about 8 mm.
 15. The integrated device of claim1, wherein the ocular contact surface is flat, convex, or concave. 16.The integrated device of claim 1, wherein the ocular contact surfacecomprises one or more traction elements.
 17. The integrated device ofclaim 1, wherein the ocular contact surface comprises an adhesivecomponent.
 18. The integrated device of claim 17, wherein the adhesivecomponent comprises a suction mechanism.
 19. The integrated device ofclaim 1, wherein the ocular contact surface comprises a materialselected from the group consisting of nylon fiber, cotton fiber,hydrogel, spongiform material, styrofoam, other foams, silicone,plastic, polypropylene, polyethylene, polytetrafluoroethylene, andcombinations thereof.
 20. The integrated device of claim 1, wherein theactuation mechanism comprises a manual actuation mechanism.
 21. Theintegrated device of claim 20, wherein the manual actuation mechanismcomprises a control lever for slidable advancement of a plunger.
 22. Theintegrated device of claim 1, wherein the actuation mechanism comprisesan automated actuation mechanism.
 23. The integrated device of claim 22,wherein the automated actuation mechanism comprises a spring-loadedactuation mechanism.
 24. The integrated device of claim 23, wherein thespring-loaded actuation mechanism is configured to deliver the activeagent into the intraocular space at a rate ranging from about 1 μl/secto about 1 ml/sec.
 25. The integrated device of claim 24, wherein thespring-loaded actuation mechanism delivers the active agent into theintraocular space at a rate ranging from about 10 μl/sec to about 100μl/sec.
 26. The integrated device of claim 23, wherein the spring-loadedactuation mechanism generates a force of about 0.1 N to about 1.0 N. 27.The integrated device of claim 23, wherein the spring-loaded actuationmechanism comprises a first spring and a second spring.
 28. Theintegrated device of claim 27, wherein the second spring is configuredto deploy a plunger and to control the rate of delivery of the activeagent.
 29. The integrated device of claim 27, wherein the first springis configured to move the conduit from a first non-deployed state to asecond deployed state and control the rate and force of deployment ofthe conduit.
 30. The integrated device of claim 1, wherein the actuationmechanism is a partially automated actuation mechanism.
 31. Theintegrated device of claim 30, wherein the partially automated actuationmechanism comprises a control lever for slidable advancement of aplunger.
 32. The integrated device of claim 30, wherein the partiallyautomated actuation mechanism comprises a spring-loaded actuationmechanism.
 33. The integrated device of claim 32, wherein thespring-loaded actuation mechanism is configured to deliver the activeagent into the intraocular space at a rate ranging from about 1 μl/secto about 1 ml/sec.
 34. The integrated device of claim 32, wherein thespring-loaded actuation mechanism delivers the active agent into theintraocular space at a rate ranging from about 10 μl/sec to about 100μl/sec.
 35. The integrated device of claim 32, wherein the spring-loadedactuation mechanism generates a force of about 0.1 N to about 1.0 N. 36.The integrated device of claim 32, wherein the spring-loaded actuationmechanism comprises a first spring and a second spring.
 37. Theintegrated device of claim 36, wherein the second spring is configuredto deploy a plunger and to control the rate of delivery of the activeagent.
 38. The integrated device of claim 36, wherein the first springis configured to move the conduit from a first non-deployed state to asecond deployed state and control the rate and force of deployment ofthe conduit.
 39. The integrated device of claim 1, wherein the actuationmechanism is a pneumatic actuation mechanism.
 40. The integrated deviceof claim 1, wherein the active agent is selected from the groupconsisting of steroidal anti-inflammatories, nonsteroidalanti-inflammatories, anti-infectives, anti-allergens, cholinergicantagonists and agonists, adrenergic antagonists and agonists,anti-glaucoma agents, neuroprotection agents, agents for cataractprevention or treatment, anti-proliferatives, anti-tumor agents,complement inhibitors, vitamins, growth factors, agents to inhibitgrowth factors, gene therapy vectors, chemotherapy agents, proteinkinase inhibitors, small interfering RNAs, analogs, derivatives, andmodifications thereof, and combinations thereof.
 41. The integrateddevice of claim 1, wherein the active agent is selected from the groupconsisting of ranibizumab, bevacizumab, pegaptanib, dexamethasone,dexamethasone sodium phosphate, triamcinolone, triamcinolone acetonide,fluocinolone, taxol-like drugs, aflibercept, anecortave acetate, andlimus family compounds.
 42. The integrated device of claim 36, whereinthe limus family compounds are selected from the group consisting ofsirolimus, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, zotarolimus,CCI-779, AP23841, and ABT-578, analogs, derivatives, conjugates, salts,and modifications thereof, and combinations thereof.
 43. The integrateddevice of claim 1, wherein the reservoir is made from a cyclic olefinseries resin.
 44. The integrated device of claim 40, wherein thereservoir lacks silicone oil or one of its derivatives.
 45. Theintegrated device of claim 1, wherein the measuring component isattached to the ocular contact surface.
 46. The integrated device ofclaim 1, wherein the measuring component comprises one or more radiallyextending members.
 47. The integrated device of claim 46, wherein theone or more radially extending members comprises a raised distal tip.48. The integrated device of claim 46, wherein the one or more radiallyextending members is flexible.
 49. The integrated device of claim 48,wherein the measuring component comprises a positional indicatorcomponent.
 50. The integrated device of claim 1, wherein the reservoiris preloaded with the active agent.
 51. The integrated device of claim3, wherein one of the proximal end and distal end of the dynamic sleeveis tapered.
 52. A method for intraocular drug delivery comprising:positioning an ocular contact surface of an integrated device on thesurface of an eye using a measuring component to determine the locationof an injection site, the integrated device further comprising ahousing, a dispensing member a dynamic resistance component, a reservoirfor holding an active agent, and an actuation mechanism; applyingpressure against the surface of the eye at a target injection site usingthe dynamic resistance component; and delivering an active agent fromthe reservoir into the eye by activating the actuation mechanism,wherein the steps of positioning, applying, and delivering are completedwith one hand.
 53. The method of claim 52, wherein the injection site isbetween about 1 mm anterior to the limbus and about 6 mm posterior tothe limbus.
 54. The method of claim 52, wherein the injection site isbetween about 3 mm to about 4 mm posterior to the limbus.
 55. The methodof claim 52, wherein the active agent is preloaded in the reservoir. 56.The method of claim 52, wherein the active agent is loaded into thereservoir using a drug loading mechanism.
 57. The method of claim 52,wherein the active agent is selected from the group consisting ofsteroidal anti-inflammatories, nonsteroidal anti-inflammatories,anti-infectives, anti-allergens, cholinergic antagonists and agonists,adrenergic antagonists and agonists, anti-glaucoma agents,neuroprotection agents, agents for cataract prevention or treatment,anti-proliferatives, anti-tumor agents, complement inhibitors, vitamins,growth factors, agents to inhibit growth factors, gene therapy vectors,chemotherapy agents, protein kinase inhibitors, small interfering RNAs,analogs, derivatives, conjugates, and modifications thereof, andcombinations thereof.
 58. The method of claim 52, wherein the activeagent is selected from the group consisting of ranibizumab, bevacizumab,pegaptanib, dexamethasone, dexamethasone sodium phosphate,triamcinolone, triamcinolone acetonide, fluocinolone, taxol-like drugs,aflibercept, anecortave acetate, and limus family compounds.
 59. Themethod of claim 58, wherein the limus family compounds are selected fromthe group consisting of sirolimus, SDZ-RAD, tacrolimus, everolimus,pimecrolimus, zotarolimus, CCI-779, AP23841, and ABT-578, analogs,derivatives, conjugates, salts, and modifications thereof, andcombinations thereof.
 60. The method of claim 52, wherein the activeagent is used to treat an ocular condition selected from the groupconsisting of macular edema, cystoid macular edema, diabetic macularedema, post-operative macular edema, retinal edema, age-related maculardegeneration, BRVO, CRVO, uveitis, and central serous chorioretinopathy.61. The method of claim 52, wherein the actuation mechanism delivers theactive agent into the intraocular space at a rate ranging from about 1μl/sec to about 1 ml/sec.
 62. The method of claim 52, wherein theactuation mechanism delivers the active agent into the intraocular spaceat a rate ranging from about 5 μl/sec to about 200 μl/sec.
 63. Themethod of claim 52, wherein the actuation mechanism delivers the activeagent into the intraocular space at a rate ranging from about 10 μl/secto about 100 μl/sec.
 64. The method of claim 52, wherein the actuationmechanism generates a force of about 0.1 N to about 1.0 N.
 65. Themethod of claim 52, wherein the dynamic resistance component comprises aslidable element coupled to the housing of the integrated device. 66.The method of claim 65, wherein the slidable element comprises a dynamicsleeve having a tapered proximal end and a tapered distal end.
 67. Themethod of claim 65, wherein the step of applying pressure against thesurface of the eye retracts the slidable element to expose thedispensing member.
 68. The method of claim 67, further comprising thestep of manual actuation of a plunger to deliver the active agent. 69.The method of claim 52, wherein the step of applying pressure againstthe surface of the eye comprises slidable advancement of the dynamicresistance component.
 70. The method of claim 69, wherein slidableadvancement of the dynamic sleeve generates a force between itself andthe housing ranging from 0 N to about 2 N.
 71. The method of claim 69,wherein slidable advancement of the dynamic sleeve generates a forcebetween itself and the housing ranging from about 0.1 N to about 1 N.72. The method of claim 69, wherein the slidable advancement is manuallyadjustable.
 73. The method of claim 69, wherein the slidable advancementis automatically adjustable.
 74. The method of claim 52, wherein thedynamic resistance component comprises an ocular wall tension controlmechanism.
 75. An integrated device for intraocular drug deliverycomprising: a housing sized and shaped for manipulation with one hand,the housing having a proximal end and a distal end; an ocular contactsurface at the housing distal end; a measuring component; a conduit atleast partially within the housing, the conduit having a proximal end, adistal end, and a lumen extending therethrough; an actuation mechanismcontained within the housing and operably connected to the conduit and areservoir for holding an active agent; a trigger coupled to the housingand configured to activate the actuation mechanism; and an ocular walltension control mechanism coupled to the housing.
 76. The integrateddevice of claim 75, wherein the ocular wall tension control mechanismcomprises a slidable cap having a locking mechanism.
 77. The integrateddevice of claim 76, wherein the locking mechanism is a manuallyoperated.
 78. The integrated device of claim 76, wherein the lockingmechanism is an automatically operated mechanism.
 79. The integrateddevice of claim 76, wherein the locking mechanism comprises a lockingpin.
 80. The integrated device of claim 76, wherein the slidable capcomprises one or more high traction surfaces.
 81. The integrated deviceof claim 80, wherein the one or more high traction surfaces compriseridges on an inner surface of the slidable cap.
 82. The integrateddevice of claim 75, wherein the ocular wall tension control mechanismcomprises a pressure sensor.
 83. The integrated device of claim 75,wherein the ocular wall tension control mechanism comprises a pressureaccumulator.
 84. A method for intraocular drug delivery comprising:positioning an ocular contact surface of an integrated device on thesurface of an eye using a measuring component to determine the locationof an injection site, the integrated device further comprising ahousing, a dispensing member an ocular wall tension control component, areservoir for holding an active agent, and an actuation mechanism;applying pressure against the surface of the eye at a target injectionsite using the ocular wall tension control component; and delivering anactive agent from the reservoir into the eye by activating the actuationmechanism, wherein the steps of positioning, applying, and deliveringare completed with one hand.
 85. The method of claim 84, wherein thestep of applying pressure against the surface of the eye comprisesslidable advancement of the ocular wall tension control component. 86.The method of claim 85, wherein slidable advancement of the ocular walltension control mechanism generates a force between itself and thehousing ranging from 0 N to about 2 N.
 87. The method of claim 85,wherein slidable advancement of the ocular wall tension controlcomponent generates a force between itself and the housing ranging fromabout 0.1 N to about 1 N.
 88. An injection device for intraocular drugdelivery comprising: a housing sized and shaped for manipulation withone hand, the housing having a proximal end and a distal end; an ocularcontact surface at the housing distal end; a conduit at least partiallywithin the housing, the conduit having a proximal end, a distal end, anda lumen extending therethrough; an actuation mechanism contained withinthe housing and operably connected to the conduit and a reservoir forholding an active agent; a trigger coupled to the housing and configuredto activate the actuation mechanism; and a dynamic resistance component.89. The injection device of claim 88, wherein the dynamic resistancecomponent comprises a dynamic sleeve having a proximal end, a distalend, and an inner surface.
 90. The injection device of claim 89, whereinthe proximal end and the distal end of the dynamic sleeve are tapered.91. The injection device of claim 89, wherein one of the proximal endand the distal end of the dynamic sleeve is tapered.
 92. The injectiondevice of claim 89, wherein the inner surface of the dynamic sleevecomprises ridges.
 93. The injection device of claim 88, wherein thedynamic sleeve further comprises a fine sleeve mobility controlcomponent.
 94. The injection device of claim 88, wherein the devicefurther comprises a measuring component.